New intermediates and their preparation methods and uses

Abstract

The present invention relates to the field of drug synthesis, specifically to a new intermediate and its preparation method and use. The structural formula of the new intermediate of the present invention is shown in Formula I. [Formula 1] JPEG2024500595000137.jpg43170Where R is a secondary amine protecting group. Based on the possible biosource route of morphine derivatives, the present invention uses the asymmetric transfer hydrogenation reaction and the intramolecular oxidative dearomatization Heck reaction in the process of preparing the above intermediate as the key reactions in the total synthesis according to the biomimetic synthesis policy, thereby realizing the highly efficient synthesis of morphine derivatives. The morphine derivatives are synthesized from the novel intermediates provided by the present invention, which has the characteristics of significantly reducing the synthesis steps, improving the yield, reducing waste generation, and saving production costs.

Description

[Technical field]

[0001] The present invention relates to the field of drug synthesis, specifically to a new type of intermediate, its preparation method and its application. [Background technology]

[0002] Morphine-based drugs, such as hydrocodone, oxycodone, buprenorphine, naloxone, and naltrexone, are used clinically as opioid receptor agonists for moderate to severe pain caused by severe wounds, burns, fractures, and cancer, as well as in hospice care, and as opioid receptor antagonists for treating respiratory depression, weaning from opioid narcotics, and treating alcoholism. They are recognized as basic drugs by the World Health Organization. According to statistics, morphine-based drugs account for 7 varieties in the top 200 drugs in terms of prescription usage worldwide in 2016, and have irreplaceable effects and extremely important clinical value in the drug market. According to the IQVIA database, the total production of global morphine-based drugs in 2018 was nearly 390 tons, and the sales value of formulations reached $14.5 billion. On the other hand, when the clinical consumption of morphine-based drugs in China only accounts for 2% of the world total, the sales scale of morphine-based drugs in China has reached 4.4 billion yuan. Therefore, with China's huge population base, the increasing number of cancer cases and the advancement of hospice care are becoming more and more important, and the treatment of respiratory depression, narcotic withdrawal and alcoholism are becoming more and more popular, the market demand for such drugs is expected to increase rapidly (World Health Organization, "18th WHO essential medicines list" (Geneva, Switzerland, 2013); Seya, MJ; Gelders, SF; Achara, OU; Milani, B.; Scholten, WK; Pain Palliat, J. Care Pharmacother. 2011, 25, 6).

[0003] Morphine-based drugs have the morphine nucleus as their basic structure, and in industrial production, morphine, thebaine and their analogues are extracted from poppy agricultural cultivation, and then derived drugs are produced by semi-synthesizing morphine, thebaine and their analogues. According to statistics, about 100,000 hectares of poppy are legally cultivated each year around the world to extract 800 tons of raw material (mainly morphine), meeting the demand for legal drug production and scientific research (International Narcotics Control Board, “Narcotic drugs: Estimated world requirements for 2015-statistics for 2013”, 2014). However, poppy cultivation is subject to problems such as the large-scale occupation of farmland and illegal cultivation, as well as factors such as pests, disease, and climate, and politics, making the supply variable and unstable. Thus, the existing industrial production method of morphine-based drugs not only occupies a large amount of farmland, has complicated production processes, and is expensive, but also has complicated management processes and insufficient management, which is likely to cause serious social problems.Therefore, it is of great significance to develop a new method for industrially producing morphine-based drugs based on the method of total synthesis.

[0004] The morphine molecule is a highly compact, complex five-ring fused molecule that contains five contiguous chiral centers, including one five-membered dihydrofuran ring, one nitrogen-containing bridged ring, and a benzylic quaternary carbon center, making it a star natural product molecule in the field of synthetic chemistry. In order to realize a highly efficient and practical total synthesis of morphine and to solve the source problem of morphine-based drugs, since the Gates Project Group completed the synthesis of morphine for the first time in 1952, there have been nearly 40 successful research studies on the total synthesis of morphine and other drugs worldwide (Reed, JW; Hudlicky, T. Acc. Chem. Res. 2015, 48, 674; Gum, A.; Stabile, M. In Studies in Natural Products Chemistry, Vol. 18, Elsevier, Amsterdam, 1996, pp. 43~154; Taber, DF; Neubert, TD; Schlecht, MF In Strategies and Tactics in Organic Synthesis, Vol. 5, Ed.: Harmata, M., Elsevier, London, 2004, pp. 353~389). Compared with the production of morphine-based drugs by cultivation, extraction, and semi-synthesis, these total synthesis methods have major disadvantages in terms of cost and feasibility of industrial expansion. Among many synthetic strategies, the bionic synthesis route designed based on the possible biosource pathway of morphine, that is, mimicking the catalytic action of enzymes and constructing the morphine skeleton by the oxidative radical coupling reaction of ortho-phenol, is the most ideal and efficient synthetic strategy. However, achieving the regioselectivity and high yield of this coupling reaction has been a synthetic challenge that has been difficult for mankind to achieve for the past 70 years. In 1964, inspired by the above biosource synthesis, the Barton group realized the first bionic synthesis of morphine, but the yield of the crucial coupling reaction was only 0.02% (Barton, DHR Pure Appl. Chem. 1964, 9, 35).Subsequently, the Szantay and White groups respectively achieved the biosynthesis of morphine using a phenol oxidative radical coupling strategy, but the crucial reaction yields were only 2.7% and 21% (Szantay, C.; Barczai-Beke, M.; Pechy, P.; Blasko, G.; Dornyei, GJ Org. Chem. 1982, 47, 594; White, JD; Caravatti, G.; Kline, TB; Edstrom, E.; Rice, KC; Brossi, A. Tetrahedron, 1983, 39, 2393). Only in 2018 did the Opatz group achieve this important coupling reaction electrochemically at a dilute reaction concentration (0.01M) with a moderate yield of 58-62% (Lipp, A.; Ferenc, D.; Ggtz, C.; Geffe, M.; Vierengel, N.; Schollmeyer, D.; Schafer, HJ; Waldvogel, SR; Opatz, T. Angew. Chem. Int. Ed. 2018, 57, 11055). However, due to the limitations of the substrate structure of the electrochemical reaction, the Opatz group completed the conversion of the coupling product to thebaine, a precursor of the morphine drug, through multiple conversion steps, but the subsequent cumbersome multi-step conversion process, the strict requirements for the efficiency of the electrochemical reaction and the related equipment limited the application of this synthesis method in industrial production.

[0005] In recent years, exploring the biosynthesis of morphine and its related drugs based on synthetic biology has become an emerging hotspot of research in this field. So far, the biosynthetic efficiency of morphine, thebaine and its analogues is far from meeting the demands of industrialized production (Galanie, S.; Thodey, K.; Trenchard, IJ; Filsinger, IM; Smolke, CD Science 2015, 349, 1095; Wang Pingping, Yang Chengshuai, Li Xiaodong, Jiang Yuguo, Yan Xing, Zhou Zhihua, Organic Chemistry, 2018, 38, 2199).

[0006] Looking at the history of the synthesis of morphine and its analogues, scientists have developed many new strategies and methods for constructing the morphine skeleton, but until now, the existing total synthesis methods for morphine and its derivatives still lack practical significance and production value. Extracting morphine and thebaine from opium poppy and then semi-synthesizing them is currently the only way to industrially obtain morphine-based drugs.

[0007] Therefore, there is an urgent need for a method for the total synthesis of morphine derivatives that is highly efficient, easy to operate, and can be scaled up on a large scale. Summary of the Invention

[0008] The purpose of the present invention is to overcome the problems that the industrial production method of morphine and its derivatives in the prior art not only occupies a large amount of farmland, has a complicated production process, is expensive, and is also long in the management and control process, complicated in the program, and is incomplete in the management and control, which is likely to cause serious social problems. At the same time, it overcomes the shortcomings that the total synthesis method still does not have practical significance and production value. The present invention provides a new intermediate and its preparation method, which significantly improves the yield of the final product, reduces the reaction steps, and reduces the production cost. The object of the present invention is achieved by the following technical solutions: The intermediate of the present invention has the structural formula: [ka] In the formula, R is a secondary amine protecting group. The secondary amine protecting group used in the present invention is selected mainly based on the compatibility of functional groups to avoid side reactions, such as to avoid unnecessary side reactions in the subsequent oxidation dearomatization Heck reaction, cyclization reaction, etc.

[0009] In certain embodiments, the secondary amine protecting group is preferably selected from one of the following groups: benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, methyl, methyl formate, t-butoxycarbonyl, benzyl, benzyloxycarbonyl, trifluoromethanesulfonyl, methanesulfonyl, and trimethylbenzenesulfonyl. The present invention further provides a method for the above intermediate, comprising the steps of: S1. [ka] Compound 18 is provided, and a protecting group R 1 The reaction of removing R produces compound 19. 1 is a protecting group I for a hydroxy group. S2. [ka] The compound 19 is reduced to produce compound 20. S3. [ka] Compound 20 above undergoes a cyclization reaction to produce intermediate I.

[0010] In a particular embodiment, in S1, the hydroxy-protecting group I is selected from the group consisting of p-methoxybenzyl, benzyl, acetyl, benzyloxycarbonyl, methoxymethylene, methyl, triisopropylsilyl ether, triethylsilyl ether, and tert-butyldiphenylsilyl. The hydroxy-protecting group I of the present invention is also selected based on the compatibility of functional groups to avoid side reactions.

[0011] In one embodiment, in S1, the protecting group R 1The removing agent used for removing the protecting group R of the hydroxy group of the present invention is selected from one of sodium hydrogen sulfide, sodium sulfide, sodium ethanethiol, thiophenol, sodium p-toluenesulfonate, potassium fluoride, tetrabutylammonium fluoride, acetic acid, trifluoroacetic acid, hydrobromic acid, iodotrimethylsilane, cerium trichloride, cerium ammonium nitrate, camphorsulfonic acid, p-toluenesulfonic acid, phosphorus oxychloride, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and hydrochloric acid. 1 The removers used for removing the protecting groups R of different hydroxy groups are mainly 1 For example, those skilled in the art often use sodium hydrogen sulfide, sodium sulfide, sodium ethanethiol, thiophenol, sodium p-toluenesulfonate, etc. to remove methyl groups. Those skilled in the art often use potassium fluoride, tetrabutylammonium fluoride, etc. to remove silicon protecting groups, all of which are common removal methods in the art.

[0012] and / or in S1, the protecting group R of the hydroxy group 1 The reaction solvent used for the removal of R is selected from the group consisting of N,N-dimethylacetamide, N-methylpyrrolidone, methanol, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane and acetic acid. 1 The reaction solvent used for removing R is mainly for the reasons of reducing side reactions, saving energy consumption, favoring the forward progress of the reaction, etc., and for the reasons of using different protecting groups R of the hydroxyl group. 1 The solvent used is selected for removal of the solvent and for suitability of the removal agent, both of which are reaction solvents common in the art.

[0013] And / or, in S1, the reaction temperature for removing the hydroxyl-protecting group is −50 to 150° C. 1 The temperature used for removing the protecting group R of the hydroxy group is 1The temperature can be specifically selected based on the conditions of the reaction solvent, the removing agent, etc. used for removing the , or can be rationally selected based on factors such as improving the yield, accelerating the reaction rate, and reducing side reactions. For example, when the removing agent is hydrobromic acid and the reaction solvent is N,N-dimethylformamide, the temperature is 0 to 70°C. When the removing agent is trifluoroacetic acid and the reaction solvent is dichloromethane, the temperature can be selected to be -40 to 0°C.

[0014] In addition, the selection of protective groups, reactants and their mixing ratios, reaction conditions, etc., for other reactions of the present invention can be reasonably selected by those skilled in the art according to the respective circumstances, and therefore will not be described here in detail.

[0015] In one embodiment, the molar ratio of the compound 18 to the remover in S1 is 1:3-25. And / or in S1, the scavenging agent is hydrobromic acid, trifluoroacetic acid or sodium hydrosulfide. And / or, in S1, the reaction solvent is dichloromethane, N,N-dimethylformamide or N,N-dimethylacetamide. and / or in S1, the protecting group R of the hydroxy group 1 The reaction temperature for the removal of is -40 to 150°C.

[0016] In one embodiment, in S2, the reducing agent in the reduction reaction is selected from one of sodium borohydride, lithium borohydride, lithium aluminum hydride, and lithium tri-tert-butoxyaluminum hydride. And / or, in S2, the reaction solvent for the reduction reaction is selected from one or two of methanol, ethanol, tetrahydrofuran, and dichloromethane. And / or, in S2, the reaction temperature of the reduction reaction is -10 to 40°C. In some embodiments, the molar ratio of compound 19 to the reducing agent in S2 is 1:1.8-3. And / or in S2, the reducing agent is sodium borohydride. And / or in S2, the reaction solvent is methanol and dichloromethane. And / or, in S2, the temperature of the reduction reaction is 0 to 25°C.

[0017] In some embodiments, in S3, the reaction solvent for the cyclization reaction is selected from one of N,N-dimethylformamide, N,N-dimethylformamide dimethyl acetal, acetonitrile, tetrahydrofuran, dichloromethane, and 1,4-dioxane. In S3, the cyclization agent of the cyclization reaction is selected from the group consisting of N,N-dimethylformamide dineopentyl acetal, N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, and N,N-dimethylformamide diisopropyl acetal. And / or, in S3, the reaction temperature of the cyclization reaction is 0 to 130°C. In some embodiments, the molar ratio of compound 20 to the cyclizing agent in S3 is 1:2-12. and / or in S3, the cyclization agent is N,N-dimethylformamide dimethyl acetal. And / or, in S3, the reaction solvent is tetrahydrofuran, 1,4-dioxane or N,N-dimethylformamide dimethyl acetal. The reaction rate is increased by using N,N-dimethylformamide dimethyl acetal. And / or, in S3, the reaction temperature of the cyclization reaction is 50 to 130°C.

[0018] In one embodiment, the synthesis route of compound 18 above is as follows: [ka] In the formula, R 2 is a protecting group for a hydroxy group, II, X is a halogen atom, and R 11 is a protecting group for a hydroxy group or a hydrogen atom, and R 1 is a protecting group I for a hydroxy group. R 11is a protecting group I for a hydroxy group, the steps include: 1) providing compound 15. 2) Compound 17 is produced by removing the protecting group II of the hydroxy group from compound 15. 3) The compound 17 undergoes an intramolecular oxidative dearomatization Heck reaction to produce the compound 18. R 11 When is a hydrogen atom, the above compound 15 is subjected to step 2) and step 3) after introducing a protecting group I for the hydroxy group.

[0019] In one embodiment, the hydroxy-protecting group II is one selected from the group consisting of p-methoxybenzyl, benzyl, acetyl, benzoyl, pivaloyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, and triethylsilyl.

[0020] In one embodiment, the halogen atom is one selected from a chlorine atom, a bromine atom, and an iodine atom.

[0021] In one embodiment, in step 2), the removing agent used to remove the protecting group II of the hydroxy group is selected from one or two of potassium carbonate, sodium methoxide, sodium hydroxide, potassium hydroxide, trifluoroacetic acid, hydrochloric acid, boron trichloride, acetic acid, tetrabutylammonium fluoride, tetraethylammonium fluoride, hydrobromic acid, potassium fluoride, and cesium fluoride. And / or, in step 2), the reaction solvent used to remove the protecting group II of the hydroxy group is selected from one or two of methanol, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane and water. And / or, in step 2), the reaction temperature for removing the protecting group II of the hydroxy group is -20 to 90°C.

[0022] In some embodiments, in step 2), the remover is potassium carbonate. And / or, in step 2), the reaction solvent is methanol. And / or, in step 2), the reaction temperature for removing the protecting group II of the hydroxy group is 40 to 60°C.

[0023] In one embodiment, in step 2), the remover is potassium fluoride. And / or in step 2), the reaction solvent is acetonitrile and water. And / or, in step 2), the reaction temperature for removing the protecting group II of the hydroxy group is 0 to 60°C.

[0024] In certain embodiments, in step 3), the intramolecular oxidative dearomatization Heck reaction is carried out in the presence of a reactant and a base.

[0025] In certain embodiments, in step 3), the reactants are a complex or a ligand II and a transition metal catalyst II.

[0026] In one embodiment, in step 3), the complex is Pd(PPh 3 ) 4 , Pd(PPh 3 ) 2 Cl 2 , Pd(PtBu 3 ) 2 , Pd(PCy 3 ) 2 , Pd(PPhtBu 2 ) 2 Cl 2 , [1,2-bis(diphenylphosphino)ethane]palladium dichloride, [1,3-bis(diphenylphosphino)propane]palladium dichloride, and [1,4-bis(diphenylphosphino)butane]palladium dichloride. And / or, the molar ratio of the compound 17, the complex, and the base is 1:0.025-0.5:1-3.

[0027] In certain embodiments, in step 3), the ligand II is as shown in formula (II), or a stereoisomer, tautomer, or phosphonium hydrohalide salt corresponding to formula (II). [ka] During the ceremony: R 4 and R 5 is one selected from an adamantyl group and a t-butyl group. R 6 is one selected from an alkyl group, a cycloalkyl group, an aryl group, and a heteroaryl group, and the alkyl group, the cycloalkyl group, the aryl group, and the heteroaryl group are each independently substituted with one or more hydrogen atoms, alkyl groups, halogens, cycloalkyl groups, aryl groups, and heteroaryl groups. And / or in step 3), the transition metal catalyst II is [Pd(cinnamy)Cl] 2 [Pd(allyl)Cl] 2 , Pd 2 (dba) 3 , Pd(OAc) 2 , Pd(Tfa) 2 , Pd(acac) 2 , Pd(MeCN) 2 Cl 2 , Pd(PhCN) 2 Cl 2 , PdCl 2 , Pd(Cp)(allyl), Pd(MeCN) 4 (B.F. 4 ) 2 , Pd(MeCN) 4 (OTf) 2 , Pd(cod)Cl 2 , Pd(norbornadiene)Cl 2 , Pd(TMEDA)Cl 2 and Pd(amphos)Cl 2 is selected from one of the following: And / or, the molar ratio of the compound 17, the ligand II, the transition metal catalyst II, and the base is 1:0.05-0.5:0.05-0.15:2-4.

[0028] In one embodiment, in step 3), the ligand II is preferably [ka] More preferably, in step 3), said ligand II is selected from one of the following compounds: [ka]

[0029] In some embodiments, in step 3), the base is selected from one or two of potassium tert-butoxide, lithium carbonate, sodium carbonate, cesium carbonate, silver carbonate, potassium bicarbonate, potassium carbonate, potassium tetrafluoroborate, potassium phosphate, dipotassium hydrogen phosphate, sodium t-butoxide, lithium t-butoxide, sodium hydride, potassium hydride, sodium acetate, sodium methoxide, sodium benzoate, potassium benzoate, pyridine, triethylamine, cesium fluoride, potassium hydroxide, and pivalate. And / or in step 3), the reaction solvent for the intramolecular oxidative dearomatization Heck reaction is selected from the group consisting of anisole, trifluoromethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, trimethylbenzene, dimethyl ether, ethanol, tert-butyl alcohol, toluene, chlorobenzene, xylene, 1,4-dioxane, diethylene glycol dimethyl ether, methyl tert-butyl ether, tetrahydrofuran and ethylene glycol dimethyl ether. And / or, in step 3), the concentration of compound 17 in the above intramolecular oxidative dearomatization Heck reaction is 0.05-2.5 mol / L. And / or, in step 3), the reaction temperature of the intramolecular oxidative dearomatization Heck reaction is 50-160°C.

[0030] In certain embodiments, in step 3), the base is potassium phosphate and potassium carbonate. And / or in step 3), the reaction solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide and anisole. And / or, in step 3), the concentration of compound 17 in the intramolecular Heck reaction is 0.05 to 1 mol / L. And / or, in step 3), the reaction temperature of the intramolecular Heck reaction is 60 to 150°C.

[0031] In one embodiment, the synthesis route of compound 15 is as follows: [ka] In the formula, R 2 is a protecting group II for a hydroxy group, and R 22 is a protecting group for a hydroxy group or a hydrogen atom, X is a halogen atom, and R 11 is a protecting group I for a hydroxy group or a hydrogen atom. R 22 is a protecting group II for a hydroxy group, the steps include: a, Compound 11 is provided. b. The above compound 11 is reacted by Bischler-Napieralski reaction to give compound 13. c. The compound 13 is subjected to asymmetric transfer hydrogenation to obtain a chiral tetrahydroisoquinoline type compound 14. d. Compound 14 above undergoes secondary amine protection to produce compound 15. R 22 When is a hydrogen atom, the above compound 11 is subjected to steps b, c and d after introducing a protecting group II for the hydroxy group.

[0032] In one embodiment, in step b, the Bischler-Napieralski reaction is carried out in the presence of a condensing agent and a base, and the molar ratio of the compound 11, the condensing agent, and the base is 1:0.9-1.3:1.5-2.5.

[0033] In one embodiment, the condensing agent is one selected from phosphorus oxychloride, diphosphorus pentoxide, and trifluoromethanesulfonic anhydride. And / or, in step b, the base is selected from one of 2-fluoropyridine, pyridine, 4-dimethylaminopyridine, dimethylpyridine and triethylamine. And / or, in step b, the reaction solvent of the Bischler-Napieralski reaction is selected from one of dichloromethane, dichloroethane, tetrahydrofuran and toluene. And / or, in step b, the temperature of the Bischler-Napieralski reaction is -50 to 40°C.

[0034] In certain embodiments, in step b, the condensing agent is trifluoromethanesulfonic anhydride. And / or, in step b, the base is 2-fluoropyridine. And / or, in step b, the reaction solvent is dichloromethane. And / or, in step b, the temperature of the Bischler-Napieralski reaction is -30 to 35°C.

[0035] In one embodiment, in step c, the asymmetric transfer hydrogenation reaction is carried out in the presence of chiral ligand I, hydrogen source I, and metal catalyst I. The molar ratio of compound 13, metal catalyst I, chiral ligand I, and hydrogen source I is preferably 1:0.001-0.01:0.002-0.02:1.2-3.

[0036] In one embodiment, in step c, the chiral ligand I is [ka] And / or in step c, the hydrogen source I is selected from one of the following: formic acid, ammonium formate, and a complex of formic acid with a trialkylamine. and / or in step c) said metal catalyst I is [ka] And / or, in step c, the reaction solvent of the asymmetric hydrogenation reaction is selected from one of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, dimethyl ether, tert-butyl methyl ether, trifluoroethanol, anisole, N,N-dimethylformamide, trifluoromethylbenzene, N,N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, trimethylbenzene, ethanol, tert-butyl alcohol, toluene, chlorobenzene, xylene, 1,4-dioxane, dichlorobenzene, hexafluoroisopropanol, methanol and isopropanol. And / or, in step c, the temperature of the transfer hydrogenation reaction is -10 to 40°C.

[0037] In an embodiment, in step c, the hydrogen source I is a methanol and triethylamine complex. And / or, in step c, the reaction solvent is N,N-dimethylformamide. And / or, in step c, the temperature of the transfer hydrogenation reaction is 0 to 35°C.

[0038] In some embodiments, in step d, the secondary amine protection is carried out under basic conditions, the base being selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, pyridine and 4-dimethylaminopyridine.

[0039] In some embodiments, the temperature of the secondary amine protection reaction in step d is -10 to 50°C.

[0040] In one embodiment, the method for preparing compound 11 includes the following steps: providing compound 9 and compound 5, and obtaining compound 11I through an amine acid condensation reaction, the reaction scheme is as follows: [ka] Here, R 3 is a methyl group or a hydrogen atom, X is a halogen atom, and R 22 is a protecting group II for a hydrogen atom or a hydroxy group.

[0041] In one embodiment, the amine acid condensation reaction is carried out in the presence of a condensing agent and a base. The molar ratio of the compound 9, the compound 5, the condensing agent and the base is 1-1.6:1:1-1.2:1.5-3.

[0042] In one embodiment, the condensing agent is selected from one of O-1H-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide, and 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate. and / or the base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine and pyridine. And / or, the temperature of the above-mentioned amino acid condensation reaction is -10 to 50°C.

[0043] In one embodiment, the condensing agent is O-1H-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroborate. And / or, the base is triethylamine. And / or, the temperature of the above-mentioned amino acid condensation reaction is 0 to 25°C.

[0044] In one embodiment, R in compound 11I above 3 is a protecting group for the hydroxy group, R 1 to give compound 11II, the reaction scheme being as follows: [ka] In the formula, R 1 is a protecting group for the hydroxy group, I, and R 2 is a protecting group II for a hydroxy group. The above compound 11 includes all of the structural formulas of the above compounds 11I and 11II.

[0045] In one embodiment, the method for preparing compound 9 includes the following steps: [ka] A, Compound 6 is provided. B. The above compound 6 undergoes the Henry reaction with nitromethane to produce compound 7. C. Compound 7 undergoes double bond reduction reaction to produce compound 8. D. The above compound 8 undergoes a nitro reduction reaction to produce compound 9I.

[0046] In some embodiments, in step B, compound 6 undergoes Henry reaction with nitromethane in the presence of a base catalyst, and the base is one or more of ethylenediamine, ammonium acetate, sodium hydroxide, piperidine, diethylamine, and morpholine.

[0047] In one embodiment, in step C, the reducing agent for the double bond reduction reaction is selected from the group consisting of lithium aluminum hydride, sodium borohydride, palladium on carbon + hydrogen gas, Raney nickel + hydrogen gas, lithium borohydride, Red-Al, zinc powder and iron powder. The Raney nickel + hydrogen gas of the present invention refers to using Raney nickel as a catalyst and hydrogen gas as a hydrogen source to carry out hydrogenation reduction. The palladium on carbon + hydrogen gas refers to using palladium on carbon as a catalyst and hydrogen gas as a hydrogen source to carry out hydrogenation reduction, both of which are reducing agents commonly used by those skilled in the art. And / or, in step C, the reaction solvent for the double bond reduction reaction is selected from one of ethanol, ethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, toluene, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether. And / or, in step C, the temperature of the double bond reduction reaction is -10 to 10°C.

[0048] In some embodiments, in step C, the molar ratio of compound 7 to the reducing agent is 1:1-3. And / or in step C, the reducing agent is sodium borohydride. And / or, in step C, the reaction solvent is ethanol and tetrahydrofuran. And / or in step C, the temperature of the reduction reaction is 0°C.

[0049] In one embodiment, in step D, the reducing agent for the nitro group reduction reaction is selected from one of lithium aluminum hydride, sodium borohydride, palladium on carbon + hydrogen gas, Raney nickel + hydrogen gas, lithium borohydride, Red-Al, zinc powder, and iron powder. And / or in step D, the reaction solvent for the nitro group reduction reaction is selected from one of ethanol, ethyl ether, isopropyl ether, methyl tert-butyl ether, tetrahydrofuran, 1,4-dioxane, toluene, ethylene glycol dimethyl ether, and diethylene glycol dimethyl ether. And / or, in step D, the temperature of the nitro group reduction reaction is -10 to 80°C.

[0050] In some embodiments, the molar ratio of compound 8 to the reducing agent in step D is 1:1-3. And / or in step D, the reducing agent is Raney nickel + hydrogen gas. And / or in step D, the reaction solvent is ethanol. And / or, in step D, the temperature of the reduction reaction is 10 to 80°C.

[0051] In one embodiment, the compound 9I can be further converted to compound 9II by hydroxyl group protection reaction, the reaction scheme of which is as follows: [ka] Among them, R 2 is a protecting group II for a hydroxy group. It should be noted that the above compound 9 includes all of the structural formulas of the above compound 9I and the above compound 9II.

[0052] In one embodiment, the hydroxyl group protection reaction of compound 9I is carried out under basic conditions, and the base used in the basic conditions is selected from one or two of 4-dimethylaminopyridine, sodium hydride, triethylamine, pyridine and imidazole. And / or the reaction solvent for the hydroxy group protection reaction of compound 9I is selected from the group consisting of dichloromethane, dichloroethane, tetrahydrofuran and toluene. And / or, the temperature of the hydroxyl group protection reaction of the above compound 9I is 0 to 40°C.

[0053] In one embodiment, the method for preparing compound 5 includes the following steps: [ka] In the formula, R 3 is a methyl group or a hydrogen atom. (1) Compound 1 is provided. (2) The above compound 1 is subjected to a halogenation reaction to produce compound 2. (3) The compound 2 is subjected to a Wittig reaction to produce compound 3. (4) The compound 3 is hydrolyzed to produce the compound 4. (5) The above compound 4 is subjected to an oxidation reaction to produce compound 5.

[0054] The present invention further provides the use of said intermediate or said process in the preparation of morphine and morphine derivatives. In some embodiments, the morphine derivatives include one of codeine, oxycodone, hydrocodone, buprenorphine, naloxone, naltrexone, and nalbuphine.

[0055] In some embodiments, intermediate I can be further reacted to produce codeine, comprising the steps of: A) The above intermediate I undergoes hydrolysis under acidic conditions to produce compound 22. [ka] B) The secondary amine protecting group R is removed from compound 22 above, with simultaneous reduction of the carbonyl group to form compound 23. [ka] C) The above compound 23 undergoes reductive N-methylation to produce codeine 24. [ka]

[0056] In certain embodiments, in step A), the acid in the hydrolysis reaction is selected from one or more of hydrogen bromide, sulfuric acid, boron trichloride, boron tribromide, silica gel, hydrochloric acid, p-toluenesulfonic acid, camphorsulfonic acid, acetic acid, and trifluoroacetic acid. And / or in step A), the solvent for the hydrolysis reaction is one or more of dibutyl ether, chloroform, isopropanol, ethanol, tetrahydrofuran, ethylene glycol dimethyl ether, methanol, dichloromethane and water. And / or, in step A), the reaction temperature of the hydrolysis reaction is -40 to 80°C.

[0057] In one embodiment, in step B), the reactant used in the removal of the secondary amine protecting group and the reduction of the carbonyl group is at least one selected from Red-Al, sodium-naphthalene, lithium aluminum hydride, and magnesium powder. And / or, in step B), the molar ratio of the compound 22 to the reactant is 1:2-6. And / or in step B), in the process of removing the secondary amine protecting group and the process of reducing the carbonyl group, the reactant used is selected from at least one of tetrahydrofuran, ethylene glycol dimethyl ether and toluene. And / or, in step B), the reaction temperature is 25-80° C. in the process of removing the secondary amine protecting group and the process of reducing the carbonyl group.

[0058] In some embodiments, in step C), the reactant for the reductive N-methylation reaction is selected from two or more of paraformaldehyde, aqueous formaldehyde, and sodium borohydride. And / or, in step C), the molar ratio of the compound 23 to the reactant is 1:1-3. And / or, in step C), the reaction solvent for the reductive N-methylation reaction is selected from at least one of methanol, ethanol, tetrahydrofuran, and acetic acid. And / or, in step C), the reaction temperature of the reductive N-methylation reaction is 25 to 60°C.

[0059] In one embodiment, intermediate I above can be further reacted to produce oxycodone, comprising the steps of: a) The above intermediate I undergoes an oxa-DA reaction to produce compound 25. The oxa-DA reaction of the present invention specifically refers to an oxa-Diels-Alder reaction. [ka] b) Compound 25 is subjected to catalytic hydrogenation to produce compound 26. [ka] c) Removal of the secondary amine protecting group from compound 26 and simultaneously reducing the carbonyl and alkenyl groups to form compound 27. [ka] d) The above compound 27 is subjected to a reductive N-methylation reaction to produce compound 28. [ka] e) The above compound 28 can be selectively oxidized to give oxycodone 29. [ka]

[0060] In one embodiment, in step a), the oxada reaction is carried out under light irradiation conditions, the light source of the light irradiation conditions being selected from one of natural light and LED light.

[0061] In certain embodiments, in step a), the oxa-DA reaction is carried out in the presence of an oxidizing agent and a photocatalyst.

[0062] In one embodiment, in step a), the photocatalyst is tetraphenylporphyrin. And / or in step a), the oxidizing agent is selected from the group consisting of oxygen, formic acid+hydrogen peroxide, acetic acid+hydrogen peroxide, tert-butyl hydroperoxide and metachloroperbenzoic acid. And / or, in step a), the reaction solvent for the OXA-DA reaction is selected from one of N,N-dimethylformamide, tetrahydrofuran, dichloromethane, dichloroethane and toluene. And / or, in step a), the temperature of the oxa-DA reaction is 0-30°C.

[0063] In one embodiment, in step a), the molar ratio of the intermediate I to the photocatalyst is 1:0.1-0.3. And / or in step a), said oxidizing agent is oxygen. And / or, in step a), the reaction solvent is dichloromethane. And / or, in step a), the temperature of the oxa-DA reaction is 10-30°C.

[0064] In certain embodiments, in step b), the catalyst for the catalytic hydrogenation reaction is selected from palladium on carbon, palladium chloride, and palladium hydroxide. And / or in step b), the reaction solvent of said catalytic hydrogenation reaction is selected from one or more of methanol, ethanol, dichloromethane, dichloroethane, ethyl acetate, isopropanol, formic acid and water. And / or, in step b), the hydrogen pressure in the catalytic hydrogenation reaction is 1-25 atm. And / or, in step b), the temperature of the catalytic hydrogenation reaction is 0-80°C.

[0065] In some embodiments, in step b), the molar ratio of compound 25 to the catalyst is 1:0.1-0.3. And / or in step b), the catalyst is palladium on carbon. And / or in step b), the reaction solvent is isopropanol, water and formic acid. And / or, in step b), the hydrogen pressure in the catalytic hydrogenation reaction is 6-12 atm. And / or, in step b), the temperature of the catalytic hydrogenation reaction is 10-40°C.

[0066] In some embodiments, in step c), the reactant used in removing the secondary amine protecting group and reducing the carbonyl and alkenyl groups is selected from one of Red-Al, lithium aluminum hydride, magnesium powder, and sodium-naphthalene. And / or in step c), the reaction solvent used in the process of removing the secondary amine protecting group and the process of reducing the carbonyl and alkenyl groups is selected from one of tetrahydrofuran, ethylene glycol dimethyl ether and toluene. And / or, in step c), the reaction temperature is 25-80° C. during the process of removing the secondary amine protecting group and the process of reducing the carbonyl group and the alkenyl group.

[0067] In some embodiments, in step c), the molar ratio of compound 26 to the reactant is 1:3-6. And / or in step c), the reactant is lithium aluminum hydride. And / or in step c), the reactant is tetrahydrofuran. And / or in step c), the reaction temperature is 40-70°C.

[0068] In some embodiments, in step d), the reactants of the reductive N-methylation reaction are selected from one of the following: paraformaldehyde+sodium borohydride, aqueous formaldehyde+sodium borohydride. And / or, in step d), the reaction solvent for the reductive N-methylation reaction is selected from one of methanol, ethanol, tetrahydrofuran, and acetic acid. And / or, in step d), the temperature of the reductive N-methylation reaction is 25-60°C.

[0069] In some embodiments, in step d), the molar ratio of compound 27 to reactant is 1:2-5. And / or in step d), the reactants are paraformaldehyde+sodium borohydride. And / or, in step d), the reaction solvent is methanol. And / or, in step d), the temperature of the reductive N-methylation reaction is 10-40°C.

[0070] In one embodiment, in step e), the oxidizing agent of the selective oxidation reaction is selected from one of the following: Dess-Martin oxidizing agent, 2-iodobenzoic acid, oxalyl chloride + dimethyl sulfoxide, acetic anhydride. And / or, in step e), the reaction solvent for the selective oxidation reaction is selected from one of dichloromethane, ethyl acetate and dimethylsulfoxide. And / or, in step e), the temperature of the selective oxidation reaction is -10 to 40°C.

[0071] In some embodiments, in step e), the molar ratio of compound 28 to the oxidizing agent is 1:3-5. And / or in step e) said oxidizing agent is a Dess-Martin oxidizing agent. And / or, in step e), the reaction solvent is dichloromethane. And / or in step e), the temperature is 0-30°C.

[0072] In one embodiment, intermediate I above is further reacted to produce naltrexone, comprising the steps of: 1. The use according to claim 53, comprising preparing compound 27, and reacting compound 27 with cyclopropanecarboxaldehyde through reductive amination to produce compound 30. [ka] 2. The above compound 30 is selectively oxidized to produce compound 31. [ka] 3. The above compound 31 is subjected to a demethylation reaction to give naltrexone 32. [ka]

[0073] In some embodiments, in step 1, the reactants of the reductive amination reaction are selected from one of cyclopropanecarboxaldehyde + sodium borohydride, cyclopropanecarboxaldehyde + sodium cyanoborohydride, and cyclopropanecarboxaldehyde + sodium triacetoxyborohydride. And / or, in step 1, the reaction solvent for the reductive amination reaction is selected from one of methanol, ethanol, tetrahydrofuran, 1,2-dichloroethane, and acetic acid. And / or, in step 1, the temperature of the reductive amination reaction is 25 to 60°C.

[0074] In some embodiments, in step 1, the molar ratio of compound 27 to the reactant is 1:2-5. And / or in step 1, the reactants are cyclopropanecarboxaldehyde+sodium borohydride. And / or, in step 1, the reaction solvent is methanol. And / or, in step 1, the temperature of the reductive amination reaction is 10 to 40°C.

[0075] In one embodiment, in step 2, the oxidizing agent in the selective oxidation reaction is selected from one of the following: Dess-Martin oxidizing agent, 2-iodobenzoic acid, oxalyl chloride + dimethyl sulfoxide, and acetic anhydride. And / or, in step 2, the reaction solvent for the selective oxidation reaction is selected from the group consisting of dichloromethane, ethyl acetate and dimethylsulfoxide. And / or, in step 2, the temperature of the selective oxidation reaction is -10 to 40°C.

[0076] In one embodiment, in step 2, the molar ratio of the compound 30 to the oxidizing agent is 1:3-5. And / or in step 2, the oxidizing agent is a Dess-Martin oxidizing agent. And / or, in step 2, the reaction solvent is dichloromethane. And / or, in step 2, the temperature is 0 to 30°C.

[0077] In one embodiment, in step 3, the demethylation reagent used in the demethylation reaction is selected from one or two of boron tribromide, hydrobromic acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, thiophenol, isopropyl mercaptan, sodium ethanethiol, potassium tert-butoxide, potassium hydroxide, potassium carbonate, potassium hydride, sodium hydride, and sodium ethoxide. And / or, in step 3, the reaction solvent for the demethylation reaction is selected from one or two of dichloromethane, chloroform, water, methanol, ethanol, diethylene glycol, ethylene glycol, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, chlorobenzene, and hexamethylphosphoric triamide. And / or, in step 3, the temperature of the demethylation reaction is -78 to 230°C.

[0078] In one embodiment, in step 3, the molar ratio of compound 31 to the demethylating agent is 1:3-8. And / or, in step 3, the demethylating agent is boron tribromide. And / or, in step 3, the reaction solvent is chloroform. And / or, in step 3, the temperature is 0 to 30°C.

[0079] In one embodiment, intermediate I can be further reacted to produce naloxone, comprising the steps of: i. preparing compound 27 according to the use of claim 53, The above compound 27 and allyl bromide are subjected to an alkylation reaction to produce compound 33. [ka] ii) The above compound 33 is selectively oxidized to produce compound 34. [ka] iii. The above compound 34 undergoes a demethylation reaction to give naloxone 35. [ka]

[0080] In one embodiment, in step i, the base for the N-alkylation reaction is selected from one or two of potassium carbonate, sodium carbonate, sodium bicarbonate, triethylamine, and diisopropylethylamine. And / or, in step i, the N-alkylation reaction solvent is selected from one or two of N-methylpyrrolidone, tetrahydrofuran, acetone, and water. And / or, in step i, the temperature of the N-alkylation reaction is 25-80°C.

[0081] In some embodiments, in step i, the molar ratio of the compound 27 to allyl bromide to base is 1:2-5:1.2-2. And / or, in step i, the base is triethylamine. And / or, in step i, the reaction solvent is N-methylpyrrolidone and water. And / or, in step i, the temperature of the N-alkylation reaction is 50-70°C.

[0082] In one embodiment, in step ii, the oxidizing agent in the selective oxidation reaction is selected from the group consisting of Dess-Martin oxidizing agent, 2-iodoxybenzoic acid, oxalyl chloride + dimethyl sulfoxide, and acetic anhydride. And / or, in step ii, the reaction solvent for the selective oxidation reaction is selected from one of dichloromethane, ethyl acetate and dimethylsulfoxide. And / or, in step ii, the temperature of the selective oxidation reaction is -10 to 40°C.

[0083] In some embodiments, in step ii, the molar ratio of compound 33 to the oxidizing agent is 1:3-5. And / or in step ii, the oxidizing agent is a Dess-Martin oxidizing agent. And / or, in step ii, the reaction solvent is dichloromethane. And / or, in step ii, the temperature is 0 to 30°C.

[0084] In one embodiment, in step iii, the demethylation reagent used in the demethylation reaction is selected from one or two of boron tribromide, hydrobromic acid, oxalic acid, methanesulfonic acid, trifluoromethanesulfonic acid, thiophenol, isopropyl mercaptan, sodium ethanethiol, potassium tert-butoxide, potassium hydroxide, potassium carbonate, potassium hydride, sodium hydride, and sodium ethoxide. And / or, in step iii, the reaction solvent for the demethylation reaction is selected from one or two of dichloromethane, chloroform, water, methanol, ethanol, diethylene glycol, ethylene glycol, N-methylpyrrolidone, N,N-dimethylformamide, N,N-dimethylacetamide, toluene, chlorobenzene, and hexamethylphosphoric triamide. And / or, in step iii, the temperature of the demethylation reaction is -78 to 230°C.

[0085] In one embodiment, in step iii, the molar ratio of the compound 31 to the demethylating agent is 1:3-8. And / or, in step iii, the demethylating agent is boron tribromide. And / or, in step iii, the reaction solvent is chloroform. And / or, in step iii, the temperature is 0 to 30°C.

[0086] It is to be understood that the total synthetic method of the present invention is not limited to the synthesis of oxycodone or codeine, but other structurally similar morphine derivatives (opioids), such as buprenorphine, dihydroetorphine, etc., can be prepared from key intermediate I using synthetic methods and routes similar to the synthesis of naloxone, naltrexone, oxycodone and codeine.

[0087] The beneficial effects of the present invention are as follows: 1. The present invention provides a total synthesis method for intermediates, especially for the representative codeine, in which the reaction substrate can be effectively converted into the desired product under the designed reaction conditions, and a highly efficient synthesis effect is achieved with high chemical and optical yields (a total of 12 steps from the amino acid condensation reaction in the shortest possible time, a total yield of 29%, and 99.9% ee). 2. The intermediate provided by the present invention can be used to prepare codeine through a few simple steps of conversion, and the prepared codeine can be further converted into morphine in one step, achieving the effects of high reaction yield and easy operation. 3. In the total synthesis method of oxycodone of the present invention, the intramolecular oxidative dearomatization Heck reaction in preparing the above intermediate is the key reaction. Due to the high reaction activity of the reactive site, it can be efficiently converted into the desired product after the reaction substrate and catalyst react with each other, with a yield of up to 82%, which is significantly improved compared with the previously reported methods. 4. The total synthesis method of the present invention is easy to operate, and most of the synthetic intermediates can be directly subjected to subsequent reactions without further separation and purification, thereby realizing the continuous operation of multi-step reactions. Specifically, compared with the literature report (Qin, Y. CCS Chem. 2021, 3, 1376;), the synthesis steps of codeine were reduced from 17 steps to 12 steps, and the yield increased from 14% to 29%, the synthesis steps of oxycodone were reduced from 17 steps to 13 steps, and the yield increased from 11% to 18%. The synthesis steps of naloxone were reduced from 21 steps to 14 steps, and the yield increased from 5% to 14%, and the synthesis steps of naloxone were reduced from 21 steps to 14 steps, and the yield increased from 5% to 13%. Significantly improve the synthesis efficiency, shorten the synthesis route, reduce waste emissions, and save production costs. The codeine synthesized by the method provided by the present invention has a cost equivalent to that of cultivation and extraction. The synthesis of morphine-like drugs containing 14 hydroxyl groups, such as oxycodone, naloxone, and naltrexone, is significantly cheaper than the traditional planting, extraction and semi-synthesis synthesis methods. 5. The total synthesis method of the present invention has mild reaction conditions, simple post-reaction treatment and easy operation, which is suitable for large-scale preparation of the drug. 6. The total synthesis method of the present invention can also be used to synthesize other opioid drugs with similar structures, which will help change the current situation in which traditional opioid drugs mainly rely on artificial cultivation of poppy to obtain thebaine, and will be beneficial for the management and safe production of these drugs. 7. The intermediates of the present invention are used in the synthesis of codeine, oxycodone, naloxone and naltrexone, and the reagents used are all common chemical reagents, and do not need to be specially prepared. At the same time, the reaction conditions are not strict, and the sensitivity to substances such as water and oxygen is not high. In addition, the post-treatment of each reaction step is simple, and the operation is good. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0088] The following describes the technical solutions of the present invention in more detail, but the protection scope of the present invention is not limited to the following. Example 1 A method for preparing compound 5, comprising the steps of: 3 For example, compound 5a is synthesized when is H and X is bromine. It includes the following steps: [ka] Isovanillin 1a (150 g, 0.986 mol, 1.0 equiv.) was dissolved in dichloromethane (2500 mL) and cooled to 0° C. in an ice bath. Dibromohydantoin (155 g, 0.542 mol, 0.55 equiv.) was gradually added thereto in small portions with stirring, and the reaction solution was then warmed to room temperature to react. After the complete disappearance of the raw material was detected by TLC (about 4 hours), the reaction solution was cooled to 0° C. and saturated Na 2 S 2 O 3 The reaction was quenched by adding aqueous solution (500 mL) and stirred at 0° C. for 1 h. After the precipitate was completely precipitated, it was filtered and the filter cake (500 mL×3) was washed with water. The obtained off-white solid 2a was collected and dried in an oven at 90° C. for 5 h and then further stirred for 6 h (50 o C) Dry in vacuum and use as is in the next reaction (193 g, 85% yield). Ph 3 P + CH 2 OMeCl -(888g, 2.59mol, 3.1equiv) was dispersed in dry tetrahydrofuran (2500mL) and cooled to 0°C in an ice bath, then t-BuOK (272g, 2.42mol, 2.9equiv.) was slowly added to the mixture suspension, turning the reaction solution orange-red, and vigorously stirred for 45 minutes. Compound 2a (193g, 0.835mol, 1.0equiv.) obtained in the previous step was gradually added in batches to the mixture suspension, and the reaction temperature naturally rose from 0°C to 20°C. After the raw material was completely disappeared by TLC (about 1 hour), the reaction temperature was lowered to 0°C again, and water (1000mL) was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (1000mL x 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a reddish-brown crude product of compound 3a, which was used directly in the next reaction without purification. The crude product of compound 3a was dissolved in a mixture of 1M HCl / acetone (v / v=1:1, 3000 mL) and diluted with 80 o After the raw material is completely disappeared by TLC observation (about 3 hours), it is cooled to room temperature, acetone is removed under reduced pressure, the resulting mixture is extracted with ethyl acetate (2000mL x 3), the organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure to obtain the crude product of brownish-brown compound 4a, which is used directly in the subsequent reaction without purification. The crude product 4a was dissolved in t-BuOH / H 2 HO (v:v = 1:1, 2000 mL) and place in an ice bath for 0 o Cool to 30°C and add NaH 2 PO 4 2H 2 O (261 g, 1.67 mol, 2.0 equiv.) was added in a batchwise manner, and then 2-methyl-2-butene (178 mL, 1.67 mol, 2.0 equiv.) was added. After the addition was completed, o After stirring for 10 min at C, NaClO 2 (151g, 1.67mol, 2.0equiv.) was slowly added in batches, and the reaction was allowed to heat up. After the addition was complete, o C to 20 oThe reaction temperature naturally rose to C, and after TLC showed that the raw materials had completely disappeared (about 3 hours), the reaction mixture was again cooled to 0 o The temperature is lowered to C. Saturated aqueous sodium bicarbonate is slowly added to it to quench the reaction until no bubbles are generated. t-BuOH is removed under reduced pressure, toluene (1000 mL) is added, and the mixture is stirred vigorously for 15 minutes. The aqueous layer is separated and washed with toluene (1000 mL x 5) and dichloromethane (1000 mL x 5) in succession. The pH of the aqueous layer is adjusted to 5 with 1M HCl, and then extracted with ethyl acetate (1000 mL x 5). The organic layers are combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product is dispersed in toluene (600 mL), stirred at room temperature for 2 hours, filtered to collect the solid, and recrystallized in isopropanol to obtain white solid compound 5a (87.0 g, 40% yield for three steps).

[0089] Example 2 In the method for preparing compound 5, R 3 For example, compound 5b is synthesized using Me and X as bromine. It includes the following steps: [ka] Ph 3 P + CH 2 OMeCl - (911g, 2.66mol, 3.1equiv.) was dispersed in dry tetrahydrofuran (2500mL) and cooled to 0°C in an ice bath, then t-BuOK (279g, 2.48mol, 2.9equiv.) was slowly added to the suspension, turning the reaction solution orange-red, and vigorously stirred for 45 minutes. Compound 2b (210g, 0.857mol, 1.0equiv.) was gradually added in batches to the suspension, and the reaction temperature naturally rose from 0°C to 20°C. After the raw material was completely disappeared by TLC (about 1 hour), the reaction temperature was lowered to 0°C again, and water (1000mL) was added to quench the reaction. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (1000mL x 3), and the organic layers were combined, dried over anhydrous sodium sulfate, filtered, and concentrated to obtain a red-brown crude product of compound 3b, which was used directly in the next reaction without purification. The crude product of compound 3b was dissolved in a mixture of 1M HCl / acetone (v / v=1:1, 3000 mL) and diluted with 80 o After the raw material is completely disappeared by TLC observation (about 3 hours), it is cooled to room temperature, acetone is removed under reduced pressure, the resulting mixture is extracted with ethyl acetate (2000mL x 3), the organic phase is combined, dried over anhydrous sodium sulfate, filtered, and the solvent is removed under reduced pressure to obtain the crude product of brownish-brown compound 4b, which is used directly in the subsequent reaction without purification. The crude product 4b was dissolved in t-BuOH / H 2 HO (v:v = 1:1, 2000 mL) and place in an ice bath for 0 o Cool to 30°C and add NaH 2 PO 4 2H 2 O (267 g, 1.71 mol, 2.0 equiv.) was added in a batchwise manner, and then 2-methyl-2-butene (181 mL, 1.71 mol, 2.0 equiv.) was added. After the addition was completed, o After stirring for 10 min at C, NaClO 2 (155g, 1.71mol, 2.0equiv.) was slowly added in batches, and the reaction was allowed to heat up. After the addition was complete, o C to 20 o The reaction temperature naturally rose to C, and after TLC showed that the raw materials had completely disappeared (about 3 hours), the reaction mixture was again cooled to 0 o C. Saturated aqueous sodium bicarbonate solution is slowly added to quench the reaction until no bubbles are generated. t-BuOH is removed under reduced pressure, toluene (1000 mL) is added, and the mixture is stirred vigorously for 15 minutes. The aqueous layer is separated and washed with toluene (1000 mL x 5) and dichloromethane (1000 mL x 5). The pH of the aqueous layer is adjusted to 5 with 1M HCl, and then extracted with ethyl acetate (1000 mL x 5). The organic layers are combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product is dispersed in toluene (600 mL), stirred at room temperature for 2 hours, filtered to collect the solid, and recrystallized in isopropanol to obtain white solid compound 5b (99.0 g, 42% yield for three steps).

[0090] Example 3 Preparation of Compound 9I: 22 Taking hydrogen atom as an example, compound 9a is synthesized by the following synthesis route: [ka] It includes the following steps: Vanillin 6 (200 g, 1.31 mol, 1.0 equiv.) was dissolved in CH 3 NO 2 (1000 mL), add ethylenediamine (1.0 mL) while stirring, and heat to reflux. After completion of the reaction is monitored by TLC (about 2 hours), the reaction solution is cooled to room temperature, and a large amount of yellow solid is precipitated. Filter, wash the filter cake with methanol / water (v / v=1:1) (200 mL x 3) and absolute ethanol (200 mL x 2) in sequence, collect the solid, and dry under vacuum with a water pump to obtain compound 7 (bright yellow fine needle crystals 185 g, 72% yield). Compound 7 (40.0 g, 0.205 mol, 1.0 equiv.) was dissolved in a mixture of THF / EtOH (v / v=1:1, 480 mL), cooled to 0°C in an ice bath, and added NaBH 4 (15.5g, 0.410mol, 2.0equiv.) was added gradually in batches, and 0 o C for 3 hours. After the complete disappearance of the raw material was confirmed by TLC, an aqueous solution of acetic acid (CH 3 COOH / H 2 The reaction is quenched by adding 250 mL of HO, v / v=1:4, v / v=1:4. After removing the organic solvent by distillation under reduced pressure, the residue is extracted with ethyl acetate (300 mL×3), the organic layers are combined, dried over anhydrous magnesium sulfate, filtered, concentrated, and the resulting crude product is filtered through a silica gel pad (eluent PE:EA=2:1, v / v) to obtain compound 8 (yellow oil), which is used directly in the next reaction. Compound 8 is dissolved in EtOH (400 mL), Raney-Ni (approximately 4.0 g) is added, and the mixture is placed in a high-pressure hydrogenation furnace and reacted at room temperature for 10 hours under 10 atm hydrogen pressure. The complete disappearance of the raw materials is observed by TLC. A large amount of solid is precipitated in the reaction solution, MeOH (300 mL) is added, and the mixture is heated to 70°C to dissolve the solid. The mixture is then filtered through Celite while still hot, and the filter cake is washed with MeOH (100 mL x 3). The filtrate is concentrated under reduced pressure until the solvent volume is approximately 200 mL, and a large amount of solid is precipitated. The mixture is allowed to cool at room temperature for 3 hours, filtered, and the filter cake is collected and vacuum-dried with a water pump for 1 hour (40 o C), and then vacuum-dried at room temperature for 0.5 hours using an oil pump to obtain a yellowish brown solid compound 9a (22.2 g, two-step yield 55%). Mp: 139-141°C. 1 H NMR (400 MHz, CDCl 3 )δ6.84(d,J=8.4Hz,1H),6.72-6.67(m,2H),3.87(s,3H),2.94(t,J=6.8Hz,2H),2.68(t,J=6.8Hz,2H). 13 C NMR (100 MHz, CDCl 3 )δ146.5,144.0,131.6,121.4,114.4,111.3,55.9,43.6,39.6.IR(neat):ν max =2512,1610,1496,1469,1232,1153,1128,1033,812cm -1 .HRMS(m / z):[M+H] + calculated for C 9 H 14 NO 2 + ,168.1019;found,168.1025.

[0091] Example 4 Preparation of compound 9II 22 Take TBDPS as an example to synthesize compound 9b, the synthetic route is as follows: [ka] Compound 9a (20.0 g, 0.120 mol, 1.0 equiv.) and imidazole (12.2 g, 0.179 mol, 1.5 equiv.) were dissolved in dry CH 2 Cl 2 (250 mL), stirred at room temperature for 10 minutes, and then TBDPSCl (34.5 g, 0.125 mol, 1.05 equiv.) was added. After reacting at room temperature for 5 hours, the reaction was found to be complete by TLC. This was dissolved in saturated NH 4 The reaction was quenched by adding aqueous Cl (300 mL), the resulting mixture was filtered through Celite, the filtrate was separated, and the aqueous layer was separated with CH 2 Cl 2 (100 mL × 2), the organic layers were combined, washed with saturated aqueous NaCl solution (100 mL × 2), dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The obtained crude product was purified by silica gel column chromatography (dichloromethane / methanol = 6:1, v / v, containing 0.5% aqueous ammonia) to give oily compound 9b (41.3 g, yield 85%). 1 H NMR (400 MHz, CDCl 3 )δ7.72-7.70(m,4H),7.41-7.32(m,6H),6.64(d,J=8.0Hz,1H),6.59(s,1H),6.47(dd,J= 8.0,1.6Hz,1H),3.55(s,3H),2.88(t,J=6.8Hz,2H),2.62(t,J=6.8Hz,2H),1.11(s,9H). 13 C NMR (100 MHz, CDCl 3 )δ150.4,143.5,135.4,134.8,133.6,132.5,129.5,127.6,127.4,120.6,120.0,113.0,55.4,43.2,38.9,26.7,19.7.IR(neat):ν max =3053,2933,2858,1587,1513,1264cm -1 .HRMS(m / z):[M+H] + calculated for C 25 H 32 NO 2 S + ,406.2197;found,406.2190.

[0092] Example 5 Preparation of compound 9II 22 Take TBS as an example to synthesize compound 9c, the synthesis route is as follows: [ka] The synthesis route was the same as in Example 4, except that in Example 5, TBSCL was added to obtain oily compound 9c. 1 H NMR (400 MHz, CDCl 3 )δ6.77(d,J=8.0Hz,1H),6.68-6.63(m,2H),3.79(s,3H),2.93(t,J=6.8Hz,2H),2.67(t,J=6.8Hz,2H),1.30(s,2H),0.99(s,9H),0.14(s,6H). 13 C NMR (100 MHz, CDCl 3 )δ150.8,143.3,133.2,120.9,120.7,112.8,55.5,43.6,39.7,25.7,18.4,-4.66.IR(neat):ν max =2929,2856,1578,1463,1275,1156,1126,1034,838cm -1 .HRMS(m / z):[M+H] + calculated for C 15 H 28 NO 2 S + ,282.1884;found,282.1881.

[0093] Example 6 The preparation of compound 11 was carried out by 22 is TBDPS, X is bromine, and R 11 Taking hydrogen atom as an example, compound 11a is synthesized by the following synthesis route: [ka] It includes the following steps: Compound 9b (51.3 g, 0.126 mol, 1.1 equiv.), compound 5a (30.0 g, 0.115 mol, 1.0 equiv.), and TBTU (44.3 g, 0.138 mol, 1.2 equiv.) were dissolved in dry CH 2 Cl 2 (300 mL). Add triethylamine (40.0 mL, 0.287 mol, 2.5 equiv.) in an ice bath, warm to room temperature, and react for 4 hours. When the raw material is completely consumed, detect by TLC, add saturated aqueous ammonium chloride (300 mL) to quench the reaction. Separate the organic layer, and then centrifuge the aqueous layer in CH 2 Cl 2 (400 mL x 1), combine the organic layers, wash with water (200 mL x 1) and saturated sodium chloride solution (100 mL x 1), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Dissolve the resulting crude product in ethyl acetate (300 mL), and wash with 0.1 M HCl (100 mL x 2), saturated NaHCO 3 The mixture was washed with 100 mL of ethyl acetate (100 mL x 2), water (100 mL x 1), and saturated sodium chloride solution (100 mL x 1), successively. The mixture was dried over anhydrous sodium sulfate, filtered, and concentrated. The resulting crude product was purified by silica gel column chromatography (petroleum ether / acetone = 4:1, v / v) to give white foamy solid 11a (67.1 g, yield 90%). 1 H NMR (400 MHz, CDCl 3 )δ7.71-7.68(m,4H),7.42-7.32(m,6H),6.71(q,J=8.0Hz,2H),6.56(d,J=8.0Hz,1H),6.49(d,J=2.0Hz,1H),6.29(dd,J=8.0,2.0Hz,1H ),6.01(s,1H),5.35(t,J=4.0Hz,1H),3.84(s,3H),3.59(s,2H),3.50(s,3H),3.38(q,J=6.0Hz,2H),2.59(t,J=6.9Hz,2H),1.10(s,9H). 13 C NMR (100 MHz, CDCl 3)δ170.0,150.6,146.5,143.7,135.5,133.8,132.0,129.7,127.8,127.6,122.1,120 .7,120.1,112.9,111.3,109.9,56.5,55.5,43.7,40.8,35.2,26.8,19.9.IR(neat):ν max =3297,3050,2932,2857,1650,1605,1512,1488,1111,1034,700cm -1 .HRMS(m / z):[M+H] + calculated for C 34 H 39 79 BrNO 5 S + ,648.1775;found,648.1778;C 34 H 39 81 BrNO 5 S + ,650.1755;found,650.1763.

[0094] Example 7 Preparation of compound 11, 22 is TBDPS, X is bromine, and R 11 For example, compound 11b is synthesized by the following synthesis route: [ka] Compound 9b (64.9 g, 0.160 mol, 1.1 equiv.), compound 5b (40.0 g, 0.145 mol, 1.0 equiv.), and TBTU (55.9 g, 0.174 mol, 1.2 equiv.) were dissolved in dry CH 2 Cl 2 (400 mL). Add triethylamine (50.6 mL, 0.364 mol, 2.5 equiv.) in an ice bath, warm to room temperature and react. When complete disappearance of the raw material is detected by TLC, add saturated aqueous ammonium chloride solution (400 mL) to quench the reaction. Separate the organic layer and the aqueous layer in CH 2 Cl 2(500 mL x 1), combine the organic layers, wash with water (300 mL x 1) and saturated sodium chloride solution (200 mL x 1), dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Dissolve the resulting crude product in ethyl acetate (400 mL), and wash with 0.1 M HCl (150 mL x 2), saturated NaHCO 3 The mixture was washed with 150 mL x 2, water (150 mL x 1), and saturated sodium chloride solution (150 mL x 1), dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was purified by silica gel column chromatography (petroleum ether / acetone = 4:1, v / v) to give white foamy solid 11b (87.7 g, yield 91%). 1 H NMR (400 MHz, CDCl 3 )δ7.70-7.68(m,4H),7.43-7.37(m,2H),7.37-7.30(m,4H),6.93(d,J=8.0Hz,1H),6. 76(d,J=8.0Hz,1H),6.57(d,J=8.0Hz,1H),6.51(d,J=1.8Hz,1H),6.31(dd,J=8.0,1.6 Hz,1H),5.38(t,J=4.8Hz,1H),3.820(s,3H,overlapped),3.818(s,3H,overlapped) ,3.59(s,2H),3.51(s,3H),3.39(q,J=6.0Hz,2H),2.60(t,J=6.8Hz,2H),1.10(s,9H). 13 C NMR (100 MHz, CDCl 3 )δ169.8,152.8,150.5,146.8,143.6,135.3,133.6,131.8,129.6,127.6,127.4,126.3,120 .7,120.5,120.0,112.7,111.5,60.4,56.0,55.3,43.6,40.7,35.1,26.6,19.7.IR(neat):ν max =3311,3052,2934,2858,1663,1512,1486,1265,1034,733,701cm -1 .HRMS(m / z):[M+H] + calculated for C 35 H 41 79BrNO 5S + ,662.1932;found,662.1930;C 35 H 41 81 BrNO 5 S + ,664.1911;found,664.1922.

[0095] Example 8 Preparation of compound 11, 22 is a hydrogen atom, X is bromine, and R 11 Taking Me as an example, compound 11c was synthesized by the following synthesis route: [ka] Compound 9a (2.00 g, 0.012 mol, 1.1 equiv.), compound 5b (3.00 g, 0.011 mol, 1.0 equiv.), and TBTU (4.24 g, 0.013 mol, 1.2 equiv.) were dissolved in dry CH 2 Cl 2 (30 mL). Add triethylamine (3.8 mL, 0.027 mol, 2.5 equiv.) in an ice bath, warm to room temperature, and react for 13 hours. When complete disappearance of the raw material is detected by TLC, add saturated aqueous ammonium chloride solution (30 mL) to quench the reaction. Separate the organic layer and store in CH 2 Cl 2 (20 mL × 3), combine the organic layers, and add 1 M HCl (50 mL × 2), saturated NaHCO 3 (50 mL x 1) and saturated sodium chloride solution (50 mL x 1). Dry over anhydrous magnesium sulfate, filter, and concentrate. Purify the resulting crude product by silica gel column chromatography (petroleum ether / acetone = 3:1, v / v) to give white foamy solid 11c (3.5 g, yield 75%). 1 H NMR (400 MHz, CDCl 3)δ6.96-6.50(m,5H),5.83(s,1H),5.52(s,1H),3.85(s,6H,overlapped),3.82-3.81(m,3H),3.60(m,2H),3.45-3.40(m,2H),2.67-2.64(m,2H). 13 C NMRδ169.9,152.8,146.7,146.6,144.2,130.3,127.5,126.3,121.2,120.7,114.3,111.5,111.0,60.4,56.0,55.8,43.6,40.7,35.1.IR(neat):ν max =3307,1650,1598,1523,1488,1271,1031cm -1 .HRMS(m / z):[M+H] + calculated for C 19 H 23 79 BrNO 5 + ,424.0754;found,424.0748;C 19 H 23 81 BrNO 5 + ,426.0734;found,426.0731.

[0096] Example 9 Preparation of compound 11, 22 is TBS, X is bromine, and R 11 Taking hydrogen atom as an example, compound 11d is synthesized by the following synthesis route: [ka] The synthetic route of compound 11d is as described above. For the synthetic procedure, see the method in Example 6. 1 H NMR (400 MHz, CDCl 3)δ6.77-6.73(m,2H),6.67(d,J=8.0Hz,1H),6.59-6.58(m,1H),6.48-6.46(m,1H),6.09(s,1H),5.39(m,1H),3 .90(s,3H),3.75(s,3H),3.62(s,2H),3.44(q,J=6.8Hz,2H),2.66(t,J=6.8Hz,2H),0.98(s,9H),0.13(s,6H). 13 C NMR (100 MHz, CDCl 3 )δ169.9,150.9,146.4,143.6,143.5,132.0,127.6,121.9,120.8,120.7,112 .5,111.2,109.7,56.3,55.4,43.5,40.6,35.1,25.7,18.4,-4.69.IR(neat):ν max =3300,2931,2855,1646,1604,1513,1488,1277,1231,1032cm -1 .HRMS(m / z):[M+H] + calculated for C 24 H 35 79 BrNO 5 S + ,524.1462;found,524.1464;C 24 H 35 79 BrNO 5 S + ,526.1442;found,526.1445.

[0097] Example 10 Preparation of compound 11, 22 is TBS, X is bromine, and R 11 For example, compound 11e is synthesized by the following synthesis route: [ka] The synthetic route of compound 11e is as shown in the diagram above. For the synthetic procedure, refer to the method in Example 6. 1 H NMR (400 MHz, CDCl 3)δ6.96(d,J=8.4Hz,1H),6.81(d,J=8.4Hz,1H),6.69(d,J=8.0Hz,1H),6.60(d,J=2.0Hz,1H),6.48(dd,J=8.0,2.0Hz,1H),5.44(t,J=5 .8Hz,1H),3.87(s,3H),3.84(s,3H),3.75(s,3H),3.61(s,2H),3.45(q,J=6.6Hz,2H),2.67(t,J=6.8Hz,2H),0.98(s,9H),0.13(s,6H). 13 C NMR (100 MHz, CDCl 3 )δ169.9,152.8,150.9,146.8,143.5,132.0,127.5,126.3,120.8,120.7,11 2.4,111.5,60.4,56.0,55.4,43.7,40.7,35.1,25.7,18.4,-4.7.IR(neat):ν max =3055,1669,1512,1264,1036,731cm -1 .HRMS(m / z):[M+H] + calculated for C 25 H 37 79 BrNO 5 S + ,538.1619;found,538.1622;C 25 H 37 81 BrNO 5 S + ,540.1598;found,540.1603.

[0098] Example 11 Preparation of Compound 12, comprising the steps of: 22 When is a hydrogen atom, a protecting group II for the hydroxy group is introduced into compound 11 to obtain compound 12. R 22 is a hydrogen atom, X is bromine, and R 11 For example, compound 12ca is synthesized when is Me and the protective group II of the introduced hydroxyl group is Bn. The synthetic route is as follows: [ka] Compound 11c (830 mg, 1.96 mmol, 1.0 equiv.) and anhydrous potassium carbonate (540 mg, 3.92 mmol, 2.0 equiv.) are dissolved in dry DMF (8 mL), protected with argon gas, benzyl bromide (0.35 mL, 2.94 mmol, 1.5 equiv.) is added, and the mixture is reacted at room temperature for 1 hour. TLC shows that the raw materials have reacted completely, and the mixture is quenched by adding water, and ethyl acetate (10 mL) is added to precipitate a large amount of solid. The mixture is filtered and the solid is washed with methyl tert-butyl ether (10 mL x 2). The solid is collected and dried in vacuum to obtain compound 12ca (white powdery solid 982 mg, yield 90%). Mp: 151-152 °C. 1 H NMR (400 MHz, CDCl 3 )δ7.45-7.43(m,2H),7.37(t,J=7.2Hz,2H),7.32-7.28(m,1H),6.97(d,J=8.4Hz,1 H),6.80(d,J=8.4Hz,1H),6.75(d,J=8.0Hz,1H),6.66(d,J=1.6Hz,1H),6.52(dd,J= 8.0,1.6Hz,1H),5.42(m,1H),5.12(s,2H),3.86(s,3H),3.84(s,3H,overlapped),3 .84(s,3H,overlapped),3.62(s,2H),3.45(q,J=6.4Hz,2H),2.68(t,J=7.2Hz,2H). 13 C NMR (100 MHz, CDCl 3 )δ170.0,153.0,149.9,146.9,137.4,131.9,128.6,127.9,127.7,127.4,126.5,1 20.9,120.8,114.4,112.5,111.6,71.3,56.2,56.1,43.8,40.8,35.2.IR(neat):ν max =3304,2936,1642,1592,1515,1487,1453,1266,1230,1034cm -1 .HRMS(m / z):[M+H] + calculated for C 26 H 29 79 BrNO 5+ ,514.1224;found,514.1219;C 26 H 29 81 BrNO 5 + ,516.1203;found,516.1201.

[0099] Example 12 Preparation of Compound 12, comprising the steps of: 22 When is a hydrogen atom, a protecting group II for the hydroxy group is introduced into compound 11 to obtain compound 12. R 22 is a hydrogen atom, X is bromine, and R 11 For example, compound 12cb is synthesized when is Me and the protective group II of the introduced hydroxyl group is PMB, and the synthetic route is as follows: [ka] Compound 11c (674 mg, 1.60 mmol, 1.0 equiv.) and anhydrous potassium carbonate (442 mg, 3.20 mmol, 2.0 equiv.) are dissolved in dry DMF (8 mL), protected with argon gas, PMBCl (0.33 mL, 2.40 mmol, 1.5 equiv.) is added, and the mixture is reacted at room temperature for 3 hours. TLC shows that the raw material is completely reacted, and the mixture is quenched by adding water, and ethyl acetate (10 mL) is added to precipitate a large amount of solid. The mixture is filtered and the solid is washed with methyl tert-butyl ether (10 mL x 2). The solid is collected and dried in vacuum to obtain compound 12cb (white powdery solid 788 mg, yield 84%). Mp: 144-146 °C. 1 H NMR (400 MHz, CDCl 3)δ7.36(d,J=8.8Hz,2H),6.97(d,J=8.4Hz,1H),6.90(d,J=8.4Hz,2H),6.81 (d,J=8.4Hz,1H),6.76(d,J=8.0Hz,1H),6.65(d,J=1.6Hz,1H),6.53(dd,J=8 .0,1.6Hz,1H),5.40(m,1H),5.04(s,2H),3.86(s,3H),3.84(s,3H),3.83(s, 3H),3.81(s,3H),3.62(s,2H),3.45(q,J=6.4Hz,2H),2.68(t,J=6.8Hz,2H). 13 C NMR (100 MHz, CDCl 3 )δ170.0,159.5,153.0,150.0,147.0,131.9,129.5,129.2,127.7,126.5,120.9,120 .8,114.5,114.1,112.5,111.7,71.1,56.2,56.1,55.4,43.8,40.9,35.2.IR(neat):ν max =3313,2932,1646,1591,1515,1249,1033cm -1 .HRMS (m / z):[M+H] + calculated for C 27 H 31 79 BrNO 6 + ,544.1329;found,544.1325;C 27 H 31 81 BrNO 6 + ,546.1309;found,546.1306.

[0100] Example 13 Preparation of Compound 12, comprising the steps of: 22 When is a hydrogen atom, a protecting group II for the hydroxy group is introduced into compound 11 to obtain compound 12. R 22 is a hydrogen atom, X is bromine, and R 11 For example, compound 12cc is synthesized when is Me and the protective group II of the introduced hydroxyl group is Ac, and the synthetic route is as follows: [ka] Compound 11c (1.00 g, 2.36 mmol, 1.0 equiv.) is dissolved in dry acetonitrile (20 mL), and anhydrous potassium carbonate (651.5 mg, 4.71 mmol, 2.0 equiv.) and acetic anhydride (0.27 mL, 2.83 mmol, 1.2 equiv.) are added in sequence under argon gas protection, and the mixture is reacted at room temperature for 2 hours. When TLC shows that the raw materials are completely reacted, water is added to quench the reaction, and the aqueous layer is extracted with ethyl acetate (20 mL x 4). The organic layers are combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product as a brown foamy solid. Methyl tert-butyl ether (5 mL) is added, and the mixture is stirred at room temperature for 20 minutes, filtered, and the solid is collected to obtain compound 12cc (off-white solid 957 mg, 87% yield). Mp: 128-130 °C. 1 H NMR (400 MHz, CDCl 3 )δ6.97(d,J=8.4Hz,1H),6.88(d,J=8.0Hz,1H),6.83(d,J=8.4Hz,1H),6.72(s,1H),6.66-6.61(m,1H),5.47(t,J=6.0 Hz,,1H),3.87(s,3H),3.84(s,3H),3.78(s,3H),3.63(s,2H),3.51-3.43(m,2H),2.74(t,J=7.2Hz,2H),2.30(s,3H). 13 CNMR (100MHz, CDCl 3 )δ170.0,169.2,152.9,151.0,146.8,138.3,137.7,127.5,126.4,122.7,120 .8,120.7,112.8,111.6,60.5,56.1,55.9,43.7,40.6,35.5,20.7.IR(neat):ν max =3290,2937,1761,1652,1597,1486,1268,1195,1031cm -1 .HRMS(m / z):[M+H] + calculated for C 21 H 25 79 BrNO 6+ ,466.0860;found,466.0859;C 21 H 25 81 BrNO 6 + ,468.0839;found,468.0840.

[0101] Example 14 Preparation of Compound 12, comprising the steps of: 22 When is a hydrogen atom, a protecting group II for the hydroxy group is introduced into compound 11 to obtain compound 12. R 22 is a hydrogen atom, X is bromine, and R 11 For example, compound 12cd is synthesized when is Me and the protective group II of the introduced hydroxyl group is Bz, and the synthetic route is as follows: [ka] Compound 11c (1.00 g, 2.36 mmol, 1.0 equiv.) is dissolved in dry dichloromethane (20 mL), protected with argon gas, cooled to 0°C, triethylamine (0.66 mL, 4.71 mmol, 2.0 equiv.) and benzoyl chloride (0.33 mL, 2.83 mmol, 1.2 equiv.) are added in sequence, and the mixture is heated to room temperature and reacted for 1 hour, and TLC shows that the raw materials are completely reacted. The reaction is quenched by adding saturated aqueous ammonium chloride solution, the aqueous layer is extracted with dichloromethane (20 mL x 4), the organic layers are combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure, and the obtained crude product is purified by silica gel column chromatography (petroleum ether / acetone = 10:1 to 2:1, v / v) to obtain a white solid 12cd. (1.15 g, yield 92%). Mp: 145-147°C. 1 H NMR (400 MHz, CDCl 3)δ8.23-8.17(m,2H),7.68-7.58(m,1H),7.54-7.47(m,2H),7.03-6.96(m,2H),6.85(d,J=8.4Hz,1H),6.77(d,J=1.6Hz,1H) ,6.69(dd,J=8.0,2.0Hz,1H),3.86(s,3H),3.85(s,3H),3.77(s,3H),3.65(s,2H),3.54-3.45(m,2H),2.78(t,J=7.2Hz,2H). 13 C NMR (100 MHz, CDCl 3 )δ170.0,164.8,152.9,151.3,146.8,138.5,137.7,133.5,130.2,129.4,128.5,127.5,1 26.4,122.8,120.8,120.7,112.9,111.6,60.5,56.0,55.9,43.7,40.6,35.5.IR(neat):ν max =3055,2939,1736,1665,1598,1510,1487,1264,1033,731,704cm -1 .HRMS (m / z):[M+H] + calculated for C 26 H 27 79 BrNO 6 + ,528.1012;found,528.1016;C 26 H 27 81 BrNO 6 + ,530.0996;found,530.0994.

[0102] Example 15 Preparation of Compound 12, comprising the steps of: 22 When is a hydrogen atom, a protecting group II for the hydroxy group is introduced into compound 11 to obtain compound 12. R 22 is a hydrogen atom, X is bromine, and R 11 For example, compound 12ce is synthesized by taking the case where is Me and the protective group II of the introduced hydroxyl group is Piv, and the synthetic route is as follows: [ka] Compound 11c (1.00 g, 2.36 mmol, 1.0 equiv.) was dissolved in dry dichloromethane (20 mL), protected with argon gas, cooled to 0 ° C, triethylamine (0.66 mL, 4.71 mmol, 2.0 equiv.) and pivaloyl chloride (0.35 mL, 2.83 mmol, 1.2 equiv.) were added in sequence, and the mixture was allowed to react for 2 hours at room temperature, and TLC showed that the raw materials were completely reacted. The reaction was quenched by adding saturated aqueous ammonium chloride solution, and the aqueous layer was extracted with dichloromethane (20 mL × 4), and the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether / acetone = 10: 1 to 6: 1, v / v) to obtain white solid 12ce (1.03 g, yield 86%). 1 H NMR (400 MHz, CDCl 3 )δ6.96(d,J=8.8Hz,1H),6.97-6.91(m,2H),6.70(d,J=1.6Hz,1H),6.63(dd,J=8.0,2.0Hz,1H),3.87( s,3H),3.84(s,3H),3.75(s,3H),3.63(s,2H),3.51-3.43(m,2H),2.74(t,J=6.8Hz,2H),1.35(s,9H). 13 C NMR (100 MHz, CDCl 3 )δ176.7,170.0,152.9,151.2,146.8,138.7,137.3,127.5,126.4,122.6,120.7, 120.7,112.8,111.6,60.5,56.0,55.9,43.6,40.6,39.0,35.4,27.2.IR(neat):ν max =2968,1752,1683,1598,1511,1486,1268,1114,1032cm -1 .HRMS(m / z):[M+H] + calculated for C 26 H 27 79 BrNO 6 +,528.1012;found,528.1016;C 26 H 27 81 BrNO 6 + ,530.0996;found,530.0994.

[0103] Example 16 Preparation of compound 15 (Bischler-Napieralski / asymmetric transfer hydrogenation). R 2 is TBDPS, X is bromine, and R 11 is a hydrogen atom and R is CO 2 Taking Me as an example, compound 15ab was synthesized, and the synthesis route is as follows: [ka] Solid compound 11a (100.0 mg, 0.154 mmol, 1.0 equiv.) was dissolved in dry CH 2 Cl 2 (1mL), and then 2-fluoropyridine (27uL, 0.308mmol, 2.0equiv.) and trifluoromethanesulfonic anhydride (32uL, 0.185mmol, 1.2equiv.) were added successively while stirring at 0℃. After the addition, the temperature was raised to room temperature and the reaction was continued for 10 minutes, and TLC showed that the raw materials had completely disappeared. The reaction solution was cooled to 0℃ and saturated NH 4 The reaction is quenched by adding aqueous Cl (1 mL). The organic layer is separated and the aqueous layer is washed with CH 2 Cl 2 (2 mL×3), the organic layers are combined, washed with saturated NaCl (2 mL×1), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product of compound 13a, which is used directly in the next reaction without isolation and purification. The crude product 13a is dissolved in dry and degassed DMF (2.9 mL) and stirred at room temperature. Another reaction bottle is taken, and metal catalyst (1.0 mg, 0.0154 mmol, 0.01 equiv.) and ligand (1S,2S)-(+)-Np-toluenesulfonyl-1,2-diphenylethylenediamine (1.2 mg, 0.0308 mmol, 0.02 equiv.) are added, evacuated, protected with argon gas, degassed dry DMF (40 uL) is added, and stirred at room temperature for 30 minutes, after which the mixture is added to the DMF solution of compound 13a, and stirred at room temperature for 10 minutes, followed by cooling to 0°C, and adding HCOOH / Et 3 Add N(5:2 complex) (55uL, 0.385mmol, 2.5equiv.), warm to room temperature and react for 17 hours. Completion of the reaction is detected by TLC. Cool the reaction to 0°C and add saturated NaHCO 3 The reaction is quenched by adding aqueous solution and the pH is adjusted to 9. The organic layer is separated, the aqueous layer is extracted with ethyl acetate (1 mL x 4), the organic layers are combined and washed with water (2 mL x 1) and saturated NaCl (2 mL x 1) successively, the organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the crude product of compound 14a, which is used directly in the next reaction without isolation and purification. The compound 14a was dissolved in THF / H 2 Dissolve in a mixture of 1,0 and 2,0-dihydrogen phosphate (2 mL, v / v=3:2), cool to 0°C, and add sodium dihydrogen phosphate dihydrate (96.1 mg, 0.616 mmol, 4.0 equiv.) and methyl chloroformate (0.462 mmol, 3.0 equiv.) in that order. Warm to room temperature and stir for 1 hour. After TLC shows that the raw materials have disappeared, add H 2 O was added, and the mixture was extracted with ethyl acetate (2 mL × 3). The organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product was purified by silica gel column chromatography (petroleum ether / acetone = 7:1, v / v) to give a white foamy solid 15ab (87 mg, total yield for three steps 82%, ee = 95%). HPLC conditions: OD-H column, Hexane: i-PrOH = 80:20, flow rate 1 mL / min, column temperature 25 °C, detection wavelength 254 nm, retention time of two enantiomers: t major =8.705min,tminor =6.352min. Optical rotation:[α] D 25 =-52.5(c=0.2,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ 7.77-7.70 (m, 4H), 7.46-7.33 (m, 6H), 6.72 (d, J = 8.4 Hz, 1H), 6.69-6.60 (m, 1H), 6.53 (s, 0.8H), 6.53 (s, 0.2H), 6.46-6.44 (m, 1H), 5.92 (s, 0.8H), 5.87 (s, 0.2H), 5.16-5.12 (m, 0.2H), 5.05-5.01 (m ,0.8H),4.28(dd,J=13.2,4.8Hz,0.7H),3.94-3.89(m,0.3H),3.85-3.84(m,3H),3.69(s,2.3H),3.57(d,J=6.8Hz,1. 4H),3.22-3.15(m,1H),3.12(s,2.3H),2.94-2.77(m,2H),2.68-2.49(m,2H),1.13(s,7H),1.11(s,2H,overlapped). 13 C NMR (100 MHz, CDCl 3 ,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ156.0,155.8,149.4,149.2,145.5,143.5,143.3,142.8,142.7,135.54,135.47,135.4,135.35,133.5,133.4,133.3,130.9,130.7,129.75,129.68,129.64,128.5,128.3,127.65,1 27.62,127.60,127.53,126.8,126.6,121.6,121.5,118.8,118.4,112.5,112.1,111.8,111.2,109.0,56.3,5 6.2,55.8,55.6,54.2,53.2,52.4,51.9,42.0,41.0,38.3,36.8,29.7,28.2,26.71,26.67,19.72.IR(neat):ν max=2928,2856,1692,1609,1488,1463,1262,1106,1033cm -1 ;HRMS(m / z):[M+H] + calculated for C 36 H 41 79 BrNO 6 S + ,690.1881;found,690.1880;C 41 H 45 81 BrNO 6 SSi + ,692.1861;found,692.1868.

[0104] Examples 17-21 Preparation of compound 15 (Bischler-Napieralski / asymmetric transfer hydrogenation). R 2 is TBDPS, X is bromine, and R 11 is a hydrogen atom and R is CO 2 Taking Me as an example, compound 15ab was synthesized, and the synthesis route is as follows: [ka] The synthesis steps of Examples 17-21 are all the same as those of Example 16, and the synthesis conditions such as temperature, time, reagents and their amounts are all shown in the synthesis route. The examples of each group are distinguished as follows: in the synthesis process, different ligands are used in the asymmetric hydrogenation reaction to prepare compound 14a from intermediate 13a. The results are shown in the following table: [Table 1] JPEG0007604038000048.jpg109170

[0105] Examples 22-25 Preparation of compound 15 (Bischler-Napieralski / asymmetric transfer hydrogenation). R 2 is TBDPS, X is bromine, and R 11 is a hydrogen atom and R is CO 2Taking Me as an example, compound 15ab was synthesized, and the synthesis route is as follows: [ka] In Examples 22-25, the synthesis steps of compound 15ab are the same as those in Example 16, and the synthesis conditions such as temperature, time, reagents and their amounts are all shown in the synthesis route. The difference between the examples in each group is the use of HCOOH / Et in the asymmetric hydrogenation reaction to prepare compound 14a from intermediate 13a in the synthesis process. 3 The only difference is the amount of N used. The results are shown in the following table: [Table 2] JPEG0007604038000050.jpg73170

[0106] Examples 26-29 Preparation of compound 15 (Bischler-Napieralski / asymmetric transfer hydrogenation). R 2 is TBDPS, X is bromine, and R 11 is a hydrogen atom and R is CO 2 Taking Me as an example, compound 15ab was synthesized, and the synthesis route is as follows: [ka] In Examples 26-29, the synthesis steps of compound 15ab are the same as those in Example 16, and the synthesis conditions such as temperature, time, reagents and their amounts are all shown in the synthesis route. The examples in each group are differentiated as follows: the amounts of metal catalyst and ligand used in the asymmetric hydrogenation reaction to prepare compound 14a from intermediate 13a during the synthesis process are different. The results are shown in the following table: [Table 3] JPEG0007604038000052.jpg64170

[0107] Examples 30-31 Preparation of compound 15 (Bischler-Napieralski / asymmetric transfer hydrogenation). R 2is TBDPS, X is bromine, and R 11 is a hydrogen atom and R is CO 2 Taking Me as an example, compound 15ab was synthesized, and the synthesis route is as follows: [ka] In Examples 30-31, the synthesis steps of compound 15ab are the same as those in Example 16, and the synthesis conditions such as temperature, time, reagents and their amounts are all shown in the synthesis route. The examples in each group are differentiated as follows: the types of metal catalysts used in the asymmetric hydrogenation reaction to prepare compound 14a from intermediate 13a during the synthesis process are different. The results are shown in the following table: [Table 4] JPEG0007604038000054.jpg57170

[0108] Examples 32-36 Preparation of compound 15 (Bischler-Napieralski / asymmetric transfer hydrogenation). R 2 is TBDPS, X is bromine, and R 11 is a hydrogen atom and R is CO 2 Taking Me as an example, compound 15ab was synthesized, and the synthesis route is as follows: [ka] In Examples 32-36, the synthesis steps of compound 15ab are the same as those in Example 16, and the synthesis conditions such as temperature, time, reagents and their amounts are all shown in the synthesis route. The differences between the examples in each group are as follows: the asymmetric hydrogenation reaction concentrations during the synthesis process to prepare compound 14a from intermediate 13a are different. The results are shown in the following table: [Table 5] JPEG0007604038000056.jpg86170

[0109] Example 37 Preparation of compound 15 (Bischler-Napieralski / asymmetric transfer hydrogenation). R 2 is TBDPS, X is bromine, and R 11 For example, compound 15aa is synthesized by the following synthesis route: [ka] Solid compound 11a (10.00 g, 15.42 mmol, 1.0 equiv.) was dissolved in dry CH 2 Cl 2 (100 mL), and then add 2-fluoropyridine (2.65 mL, 30.83 mmol, 2.0 equiv.) and trifluoromethanesulfonic anhydride (3.10 mL, 18.50 mmol, 1.2 equiv.) in sequence while stirring at 0°C. After the addition is complete, the temperature is raised to room temperature and the reaction is continued for 10 minutes. TLC shows that the raw materials have completely disappeared. The reaction solution is cooled to 0°C and saturated NH 4 The reaction is quenched by adding aqueous Cl (100 mL). The organic layer is separated and the aqueous layer is washed with CH 2 Cl 2 (100 mL×3), the organic layers are combined, washed with saturated NaCl (50 mL×1), dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product of compound 13a, which is used directly in the next reaction without isolation and purification. The crude product 13a is dissolved in dry and degassed DMF (46 mL) and stirred at room temperature. Another reaction bottle is taken, and metal catalyst (47.2 mg, 0.077 mmol, 0.005 equiv.) and ligand (1S,2S)-(+)-Np-toluenesulfonyl-1,2-diphenylethylenediamine (56.5 mg, 0.154 mmol, 0.01 equiv.) are added, evacuated, protected with argon gas, degassed dry DMF (4 mL) is added, and stirred at room temperature for 30 minutes, after which the mixture is added to the DMF solution of compound 12, and stirred at room temperature for 10 minutes, followed by cooling to 0 °C, and adding HCOOH / Et 3 Add N(5:2 complex) (4.90 mL, 33.9 mmol, 2.2 equiv.), warm to room temperature and react for 17 h. Completion of the reaction is detected by TLC. Cool the reaction to 0 °C and add saturated NaHCO 3The reaction is quenched by adding aqueous solution and the pH is adjusted to 9. The organic layer is separated, the aqueous layer is extracted with ethyl acetate (100 mL×4), the organic layers are combined and washed with water (50 mL×1) and saturated NaCl (50 mL×1) successively, the organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to obtain the crude product of compound 14a, which is used directly in the next reaction without isolation and purification. The compound 14a was dissolved in THF / H 2 Dissolve in a mixture of 1,000 ml ... 2 The mixture was diluted with 2,000 mL of hexane, extracted with ethyl acetate (100 mL × 3), and the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / acetone = 7:1, v / v) to obtain white foamy solid 15aa (9.34 g, total yield for three steps 77%, ee = 96%). HPLC conditions: IC-H column, Hexane: i-PrOH = 70:30, flow rate 1 mL / min, column temperature 25 °C, detection wavelength 254 nm, t major =27.883min,t minor =21.832min. Optical rotation:[α] D 25 =-119.5(c=0.44,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3)δ7.74-7.71(m,4H),7.47-7.33(m,6H),7.30-7.26(m,2H),6.95(d,J=8.0Hz,2H),6.63(d,J=8. 0Hz,1H),6.51(d,J=10.4Hz,1H),6.49(s,1H,overlapped),6.35(s,1H),5.83(s,1H),4.81(dd, J=10.0,4.4Hz,1H),3.91(dd,J=14.4,5.6Hz,1H),3.86(s,3H),3.59(s,3H),3.49-3.42(m,1H), 2.80-2.71(m,2H),2.69-2.58(m,1H),2.43(dd,J=16.0Hz,2.4Hz,1H),2.31(s,3H),1.12(s,9H); 13 C NMR (100 MHz, CDCl 3 )δ149.5,145.7,143.3,142.8,142.5,137.4,135.5,135.5,133.4,133.4,130.0,129.8,129.7,128.9,127.7,127.6,12 7.6,127.0,125.7,122.1,118.6,112.4,111.3,109.0,56.1,55.6,55.4,42.5,38.7,26.7,26.5,21.4,19.7;IR(neat):ν max =3431,2933,2857,1609,1513,1489,1442,1228,1154,1114,1033,702cm -1 ;HRMS(m / z):[M+H] + calculated for C 41 H 45 79 BrNO 6 SSi + ,786.1915;found,786.1920;C 41 H 45 81 BrNO 6 SSi + ,788.1894;found,788.1904.

[0110] Example 38 The preparation of compound 15 (Bischler-Napieralski / unremovable hydrogenation) was performed. R 2 is TBDPS, X is bromine, and R 11 For example, compound 15ac is synthesized when R is hydrogen atom and R is Cbz. The synthesis route is as follows: [ka] The synthesis route and reaction conditions of compound 15ac are shown in the figure above, using the ligand (1S,2S)-(+)-Np-toluenesulfonyl-1,2-diphenylethylenediamine. The synthesis procedure refers to the synthesis of 15ab. (Total yield of three steps: 75%, ee=97%(R)). HPLC conditions: IC00C3-QG035 column, Hexane: i-PrOH=80:20, flow rate 1mL / min, column temperature 25℃, detection wavelength 254nm, t major =10.179min,t minor =8.966min. Optical rotation:[α] D 25 =-69.0(c=0.68,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 )δ7.75-7.72(m,4H),7.43-7.22(m,9.6H),7.02-7.01(m,1.4H),6.61-6. 42(m,4H),5.87-5.76(m,1H),5.19-5.02(m,1H),4.97-4.76(m,1H),4.41 (d,J=12.4Hz,1H),4.34-3.98(m,1H),3.82-3.81(m,3H),3.68(s,2.3H), 3.59(s,0.7H),3.33-3.19(m,1H),2.92-2.47(m,4H),1.13-1.11(m,9H); 13 C NMR (100 MHz, CDCl 3)δ155.4,155.0,149.4,149.2,145.57,145.55,143.5,143.4,142.8,142.7,137.1,136.1,135.53,135.49,135.5, 135.4,133.44,133.40,133.3,130.8,130.7,129.73,129.70,129.65,128.5,128.4,128.3,128.2,127.8,127.7,1 27.64,127.62,127.60,127.5,126.7,126.6,121.54,121.51,118.8,118.5,112.5,112.2,111.8,111.4,109.00,1 08.9,66.9,66.6,56.2,55.8,55.6,54.3,53.5,41.9,41.0,38.4,36.9,28.3,28.1,26.70,26.68,19.7;IR(neat):ν max =2961,2857,1688,1487,1428,1261,1100,1031,753,700cm -1 ;HRMS(m / z):[M+H] + calculated for C 42 H 45 79 BrNO 6 S + ,766.2194;found,766.2194;C 42 H 45 81 BrNO 6 S + ,768.2174;found,768.2187.

[0111] Example 39 Preparation of compound 15 (Bischler-Napieralski / asymmetric transfer hydrogenation). R 2 is TBS, X is bromine, and R 11 is a hydrogen atom and R is CO 2 Taking Me as an example, compound 15da is synthesized, and the synthesis route is as follows: [ka] The synthesis route and reaction conditions of compound 15da are shown in the above diagram, and the synthesis procedure refers to the synthesis of compound 15ab in Example 16. The ligand used was (1R,2R)-(+)-Np-toluenesulfonyl-1,2-diphenylethylenediamine (total yield of three steps: 68%, ee=97%(S)). HPLC conditions: OD-H column, Hexane: i-PrOH=85:15, flow rate 0.5mL / min, column temperature 25°C, detection wavelength 254nm, t major =15.247min,t minor =18.434min. Optical rotation:[α] D 25 =+55.3(c=2.0,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ 6.73-6.67 (m, 2H), 6.58-6.43 (m, 1.7H), 6.43 (s, 0.3H), 5.99-5.91 (m, 1H), 5.35-5.29 (m, 1H), 4.30-4.25 (m, 0.7H), 3.91-3.87 (m, 3.3H, overlapped), 3.76-3.7 7(m,3H),3.64(s,0.8H),3.48-3.42(m,0.3H),3.35-3.28(m,0.7H,overlapped),3.26(s,2.2H),3. 24-3.07(m,1H),2.98-2.84(m,1H),2.81-2.65(m,1H),1.00(s,6H),0.95(s,3H),0.16-0.08(m,6H); 13 C NMR (100 MHz, CDCl 3,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ 156.1, 156.0, 149.81, 149.76, 145.7, 145.6, 143.4, 143.1, 143.0, 142.8, 130.79, 130.76, 128.6, 127.2, 127.0, 121.80, 121.75, 119.6, 119. 1,112.1,111.9,111.8,111.3,109.3,109.2,56.3,56.2,55.6,54.9,53.6,52.5,52.1,42 .3,41.1,39.0,37.4,28.2,25.72,25.67,18.5,18.4,-4.8,-4.8,-4.7,-4.6;IR(neat):ν max =2930,2856,1685,1512,1488,1260,1226,1033,755cm -1 ;HRMS(m / z):[M+H] + calculated for C 26 H 37 79 BrNO 6 S + ,566.1568;found,566.1565;C 26 H 37 81 BrNO 6 S + ,568.1548;found,568.1545.

[0112] Example 40 Preparation of compound 15 (Bischler-Napieralski / asymmetric transfer hydrogenation). R 2 is TBDPS, X is bromine, and R 11 For example, compound 15ba is synthesized when R is Me and R is Ts. The synthesis route is as follows: [ka] The above solid compound 11b (30.00 g, 45.27 mmol, 1.0 equiv.) was dissolved in dry CH 2 Cl 2(300 mL), and then add 2-fluoropyridine (7.8 mL, 90.54 mmol, 2.0 equiv.) and trifluoromethanesulfonic anhydride (9.2 mL, 54.32 mmol, 1.2 equiv.) in sequence while stirring at 0°C. After the addition is complete, the temperature is raised to room temperature and the reaction is continued for 10 minutes. TLC shows that the raw materials have completely disappeared. The reaction solution is cooled to 0°C and saturated NH 4 The reaction is quenched by adding aqueous Cl (300 mL). The organic layer is separated and the aqueous layer is washed with CH 2 Cl 2 (300 mL×3), the organic layers are combined, washed with saturated NaCl (100 mL×1), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure to give the crude product of yellow foamy solid 13b, which is used directly in the next reaction without isolation and purification. The crude product 13b is dissolved in dry and degassed DMF (140 mL) and stirred at room temperature. Another reaction bottle is taken, and metal catalyst (139 mg, 0.226 mmol, 0.005 equiv.) and ligand (1S,2S)-(+)-Np-toluenesulfonyl-1,2-diphenylethylenediamine (166 mg, 0.453 mmol, 0.01 equiv.) are added, evacuated, protected with argon gas, degassed dry DMF (10 mL) is added, and stirred at room temperature for 30 minutes, after which the mixture is added to the DMF solution of compound 13b, and stirred at room temperature for 10 minutes, followed by cooling to 0°C, and adding HCOOH / Et 3 Add N(5:2 complex) (14.2 mL, 99.6 mmol, 2.2 equiv.), warm to room temperature and react for 17 h. Completion of the reaction is detected by TLC. Cool the reaction to 0 °C and add saturated NaHCO 3 The reaction is quenched by adding aqueous solution and the pH is adjusted to 9. The organic layer is separated, the aqueous layer is extracted with ethyl acetate (300 mL x 3), the organic layers are combined and washed successively with water (50 mL x 1) and saturated NaCl (50 mL x 1), the organic layer is dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure to give the crude product 14b as a black foamy solid, which is used directly in the next reaction without isolation and purification. The compound 14b was dissolved in THF / H 2Dissolve in a mixture of 1,000 mL ... 2 The mixture was diluted with 200 mL of hexane, extracted with ethyl acetate (200 mL × 3), and the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (petroleum ether / acetone = 7:1, v / v) to give white foamy solid 15ba (29.9 g, total yield for three steps 84%, ee = 96%). HPLC conditions: AD-H column, Hexane: i-PrOH = 70:30, flow rate 1 mL / min, column temperature 25 °C, detection wavelength 254 nm, t major =5.585min,t minor =4.769min. Optical rotation:[α] D 25 =-117.9(c=0.8,CHCl 3 ); 1 H NMR (400MHz, CDCl 3 )δ7.73-7.70(m,4H),7.46-7.28(m,8H),6.96(d,J=8.2Hz,2H),6.70(s,2H ),6.50(s,1H),6.32(s,1H),4.89(q,J=4.8Hz,1H),3.88-3.87(m,1H,overl apped),3.84(s,3H),3.81(s,3H),3.58(s,3H),3.50-3.42(m,1H),2.83-2. 72(m,2H),2.56-2.48(m,1H),2.41-2.36(m,1H),2.30(s,3H),1.12(s,9H); 13 C NMR (100 MHz, CDCl 3)δ152.2,149.5,146.2,143.3,142.6,137.6,135.5,135.44,133.38,133.3,130.0,129.74,129.71,129.0,127.7,127.6,1 26.8,126.5,125.6,120.7,118.5,112.2,110.6,60.4,55.8,55.53,55.46,42.6,38.6,26.7,26.2,21.4,19.7;IR(neat):ν max =2933,1513,1487,1448,1261,1155,1113,1033,701cm -1 ;HRMS(m / z):[M+H] + calculated for C 42 H 47 79 BrNO 6 SSi + ,800.2071;found,800.2066;C 26 H 37 81 BrNO 6 S + ,802.2051;found,802.2050.

[0113] Example 41 Preparation of compound 15 (Bischler-Napieralski / asymmetric transfer hydrogenation). R 2 is TBDPS, X is bromine, and R 11 is Me and R is CO 2 Me as an example, compound 15bb was synthesized, and the synthesis route is shown in Example 40. The ligand used is (1S,2S)-(+)-Np-toluenesulfonyl-1,2-diphenylethylenediamine. [ka] 15bb was obtained (total yield of three steps: 81%, ee=96%). HPLC conditions: AD-H column, Hexane: i-PrOH=95:5, flow rate 0.8mL / min, column temperature 25℃, detection wavelength 254nm, t major =8.100min,t minor=10.942min. Optical rotation:[α] D 25 =-52.5(c=0.2,CHCl 3 );Optical rotation:[α] D 25 =+53.6(c=0.8,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ 7.76-7.70 (m, 4H), 7.46-7.32 (m, 6H), 6.66 (d, J = 8.4 Hz, 1H), 6.62-6.61 (m, 2H), 6.53 (s, 0.8H), 6.49 (s, 0.2H), 5.15-5.12 (m, 0.2H), 5.06-5.02 (m, 0.8H), 4.27 (dd, J = 13.2 ,4.4Hz,1H),3.84(s,2.4H),3.82(s,3.6H,overlapped),3.69(s,2.4H),3.56(d,J=8.8Hz,1.2H),3.29-3 .14(m,1H),3.11(s,2.4H),2.91-2.77(m,2H),2.68-2.56(m,2H),1.14(s,7H),1.10(s,2H,overlapped); 13 C NMR (100 MHz, CDCl 3 ,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ155.9,155.7,152.00,149.4,149.2,146.2,143.5,143.3,135.51,135.46,135.41,135.36,133.4,133.3,130.9,130.8,129.73,129.66,129.6,128.5,128.3,127.62,127.60,1 27.57,127.5,126.8,126.6,126.0,121.1,120.6,118.8,118.3,112.4,112.1,110.7,60.4,60.4,56.0,56. 0,55.8,55.5,54.3,53.2,52.4,51.9,42.1,41.1,38.4,36.8,28.20,28.15,26.71,26.68,19.7;IR(neat):ν max=2932,2857,1696,1593,1513,1486,1447,1260,1104,1032,701cm -1 ;HRMS(m / z):[M+H] + calculated for C 37 H 43 79 BrNO 6 S + ,704.2038;found,704.2037;C 26 H 37 81 BrNO 6 S + ,706.2017;found,706.2018.

[0114] Example 42 Preparation of compound 15 (Bischler-Napieralski / asymmetric transfer hydrogenation). R 2 is TBDPS, X is bromine, and R 11 For example, compound 15bc is synthesized when R is Me and R is Cbz, and the synthesis route is shown in Example 40. The ligand used is (1S,2S)-(+)-Np-toluenesulfonyl-1,2-diphenylethylenediamine. [ka] 15bc (total yield of three steps: 72%, 94% ee(R)) was obtained. HPLC conditions: ADH0CE-EK072 column, gradient elution, 0-5.5 min, Hexane: i-PrOH = 60:40 to 40:60, 5.5-25 min, Hexane: i-PrOH = 40:60, flow rate 1 mL / min, column temperature 40oC, detection wavelength 254 nm, t major =11.470min,t minor = 4.066min. Optical rotation: [α] D 25 =-66.3(c=0.76,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ 7.75-7.70 (m, 4H), 7.44-7.22 (m, 9.5H), 7.04-7.02 (m, 1.5H), 6.68-6.46 (m, 4H), 5.20-5.07 (m, 1H), 5.05-4.84 (m, 1H), 4.42-3.97 (m, 2H), 3.80-3.79 (m, 3.8H), 3.67 (d, J = 5.8Hz, 4.4H), 3.59 (s, 0.8H), 3.32-3.20 (m, 1H), 2.95-2.44 (m, 4H), 1.13-1.11 (m, 9H); 13 C NMR (100 MHz, CDCl 3 ,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ 155.3, 155.0, 152.04, 151.99, 149.4, 149.2, 146.3, 146.2, 143.44, 143.37, 137.1, 136.4, 135.51, 135.49, 135.44, 135.40, 133.4, 133.3, 130.79, 130.76, 129.73, 129.66, 128.5, 128.4, 128.3, 128.2, 127. 7,127.64,127.59,127.54,127.45,126.8,126.6,126.0,121.1,120.1,118.7,118.5,112.4,112.2,110.72,110.68,66.7 1,66.65,60.4,60.3,56.0,55.7,55.6,54.2,53.6,41.9,41.1,38.4,37.0,28.3,28.0,26.9,26.7,26.7,19.7;IR(neat):ν max =2932,2857,1697,1593,1513,1486,1427,1261,1102,1034,700cm -1 ;HRMS(m / z):[M+H] + calculated for C 43 H 47 79 BrNO 6 S + ,780.2351;found,780.2355;C 43 H 47 81 BrNO 6 S +,782.2330;found,782.2340.

[0115] Example 43 Preparation of compound 15 (Bischler-Napieralski / asymmetric transfer hydrogenation). R 2 is TBS, X is bromine, and R 11 For example, compound 15ea is synthesized when R is Me and R is Ts. The synthesis route is as follows: [ka] Compound 15ea can be obtained by starting with 11e, passing through intermediates 13e and 14e, and then introducing a Cbz protecting group. The synthesis procedure is the same as for 15aa. The reaction conditions and amounts of reagents used from 11e to 15ea are shown in the figure above. 15ea: The ligand used was (1S,2S)-(+)-Np-toluenesulfonyl-1,2-diphenylethylenediamine, and the three-stage yield was 69%, 96% ee(S). HPLC conditions: IC00C3-QG035 column, Hexane: i-PrOH=60:40, flow rate 1mL / min, column temperature 25℃, detection wavelength 254nm, t major =16.703min,t minor =13.134min. Optical rotation:[α] D 25 =-111.8(c=0.6,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ 7.44 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 6.82 (d, J = 8.4 Hz, 1H), 6.74 (d, J = 8.4 Hz, 1H), 6.46 (s, 1H), 6.40 (s, 1H), 5.16-5.12 (m, 1H), 3.89-3.87 (m, 1H, overlapped), 3.85 (s, 3H), 3.83 (s, 3H), 3.72 (s, 3H), 3.62-3.55 (m, 1H), 3.15-3.06 (m, 2H), 2.70-2.50 (m, 2H), 2.31 (s, 3H), 0.96 (s, 9H), 0.10 (s, 6H). 13 C NMR (100 MHz, CDCl 3 ,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ152.3,149.9,146.4,143.1,142.7,137.4,130.1,129.2,127.8,127.0,126.7,126.1,120.8,119.2,111.9,110.8,60.4,55.9,55.8,55.5,43.0,39.2,26.5,25.7,21.4,18.4,-4.66,-4.73.IR(neat):ν max =2931,2857,1511,1487,1259,1156,1092,1033,801cm -1 .HRMS(m / z):[M+H] + calculated for C 32 H 43 79 BrNO 6 SSi + ,676.1758;found,676.1752;C 32 H 43 79 BrNO 6 SSi + ,678.1738;found,678.1735.

[0116] Examples 44-50 Preparation of compound 15 (Bischler-Napieralski / asymmetric transfer hydrogenation). R 2 is a protecting group II for a hydroxy group, X is bromine, and R11 Take for example, where R is Me or PMB and R is a secondary amine protecting group, compound 15 is synthesized, and the synthetic route is as follows: [ka] In Example 44, R 2 is TBDPS, X is bromine, and R 11 For example, compound 15ad was synthesized when R is PMB and R is COOMe. The ligand used was (1R,2R)-(+)-Np-toluenesulfonyl-1,2-diphenylethylenediamine. The total yield of the three steps was 80%, and ee=86%(S). HPLC conditions: IC-H column, Hexane: i-PrOH=85:15, flow rate 0.8mL / min, column temperature 25℃, detection wavelength 254nm, t major =21.438min,t minor =24.448min. Optical rotation:[α] D 25 =+49.9(c=0.68,CHCl 3 ); 1 H NMR (400 MHz, CDCl 3 ,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ 7.77-7.69 (m, 4H), 7.53-7.31 (m, 8H), 6.97-6.90 (m, 2H), 6.74-6.45 (m, 4H), 5.17-5.03 (m, 1H), 4.91-4.90 (m, 2H), 4.30-4.12 (m, 1H), 3.85-3.80 (m, 6.2H), 3.67-3.56 (m, 3.6H), 3.21-3.14 (m, 1H), 3.11 (s, 2H), 2.97-2.77 (m, 2H), 2.68-2.40 (m, 2H), 1.14-1.11 (m, 9H). 13 C NMR (100 MHz, CDCl 3,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ159.6,159.4,156.0,155.8,152.2,149.4,149.2,145.2,145.1,143.5,143.3,135.53,135.48,135.44,135.39,133.5,133.3,131.0,130.8,130.3,130.2,129.72,129.65,129.4,128.5,128.4,127.64,12 7.61,127.5,126.9,126.6,126.0,121.6,121.1,118.8,118.4,113.7,113.6,112.4,112.1,110.7,74.4,74.2,56.1,56.0 ,55.7,55.6,55.32,55.28,54.3,53.2,52.4,52.0,42.2,41.1,38.4,36.9,28.22,28.15,26.74,26.71,19.7.IR(neat):ν max =2932,2858,1697,1612,1592,1513,1484,1447,1260,1106,1032,752,702cm -1 .HRMS(m / z):[M+H] + calculated for C 44 H 49 79 BrNO 7 S + ,810.2456;found,810.2450;C 44 H 49 81 BrNO 7 S + ,812.2436;found,812.2441.

[0117] In Example 45, R 2 is Bn, X is bromine, and R 11For example, compound 15ca was synthesized using the ligand (1R,2R)-(+)-Np-toluenesulfonyl-1,2-diphenylethylenediamine, with a total yield of 82% for the three steps and ee=96%(S). HPLC conditions: IC-H column, Hexane:i-PrOH=60:40, flow rate 1.0mL / min, column temperature 25℃, detection wavelength 254nm, t major =18.441min,t minor =14.962min. Optical rotation:[α] D 25 =+75.3(c=0.68,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ 7.46-7.28 (m, 5H), 6.79-6.70 (m, 2.8H), 6.61 (d, J = 12.4Hz, 1H), 6.37 (s, 0.2H), 5.31-5.23 (m, 1H), 5.14 (s, 1.5H), 4.32 (dd, J = 13.2, 4.2Hz, 0.5H), 4.34-4.3 0(m,0.7H),3.96-3.91(m,0.3H),3.88-3.82(m,9H),3.63(s,0.7H),3.45-3.38(m,0.3H),3.28(t d,J=12.8,4.0Hz,0.8H),3.21(s,2H),3.13-3.04(m,1.2H),2.92-2.76(m,2H),2.68-2.61(m,1H). 13 C NMR (100 MHz, CDCl 3,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ155.91,155.87,152.14,148.5,148.4,146.4,146.3,146.2,137.2,137.1,130.8,130.7,128.6,128.5,128.3,128.2,127.9,127.8,127.2,127.1,126.8,1 26.7,126.3,126.2,121.3,120.6,113.2,112.9,111.8,111.6,110.9,110.8,71.4,71.1,60.5,6 0.4,56.1,56.02,55.98,54.7,53.5,52.5,52.1,42.3,41.2,38.7,37.0,28.2,28.1.IR(neat):ν max =2929,1695,1594,1515,1486,1448,1256,1101,1032cm -1 .HRMS(m / z):[M+H] + calculated for C 28 H 31 BrNO 6 + ,556.1329;found,556.1326;C 44 H 49 81 BrNO 7 S + ,558.1309;found,558.1310.

[0118] In Example 46, R 2 is PMB, X is bromine, and R 11 For example, compound 15cb was synthesized when R is Me and R is COOMe. The ligand used was (1R,2R)-(+)-Np-toluenesulfonyl-1,2-diphenylethylenediamine. The total yield of the three steps was 68%, and ee=96%(S). HPLC conditions: IC-H column, Hexane:i-PrOH=60:40, flow rate 1.0mL / min, column temperature 25℃, detection wavelength 254nm, t major =30.306min,t minor =24.274min. Optical rotation:[α] D 25=+66.3(c=0.48,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 ,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ 7.38 (d, J = 8.8 Hz, 1.5 H), 7.30 (d, J = 8.4 Hz, 0.5 H), 6.92-6.86 (m, 2 H), 6.78-6.71 (m, 2.8 H), 6.62-6.59 (m, 1 H), 6.38 (s, 0.2 H), 5.33-5.25 (m, 1 H), 5.05 (s, 1.5 H), 4.85 (q, J = 12.0 Hz, 0.5 H) ,4.32(dd,J=13.2,5.6Hz,0.7H),3.98-3.91(m,0.3H),3.88-3.80(m,12H),3.63(s,0.7H),3.45-3.38(m,0.2H), 3.32-3.25(m,0.8H,overlapped),3.22(s,2.3H),3.15-3.11(m,1.2H),2.91-2.76(m,1.8H),2.68-2.61(m,1H). 13 C NMR (100 MHz, CDCl 3 ,Due to the phenomenon of amide rotational isomerization, certain signals appear in pairs) δ159.34,159.28,155.92,155.88,152.2,148.6,148.4,146.5,146.3,146.2,130.9,130.7,129.2,129.1,129.0,128.9,128.3,128.2,126.7,126.6,126.3,126.2 ,121.3,120.6,114.0,113.9,113.3,113.0,111.8,111.5,110.9,110.8,71.1,70.9,60.5,60.4,56 .1,56.0,55.96,55.3,55.2,54.7,53.5,52.5,52.1,42.3,41.2,38.7,37.0,28.2,28.1.IR(neat):ν max =3013,2935,1690,1613,1486,1451,1243,1102,748cm -1 .HRMS(m / z):[M+H] + calculated for C 29 H 33 79 BrNO 7+ ,586.1435;found,586.1434;C 29 H 33 81 BrNO 7 + ,588.1414;found,588.1420.

[0119] In Example 47, R 2 is Ac, X is bromine, and R 11 For example, compound 15cc was synthesized when R is Me and R is Ts. The ligand used was (1R,2R)-(+)-Np-toluenesulfonyl-1,2-diphenylethylenediamine. The total yield of the three steps was 84%, and ee=94%(S)(measured after removing Ac). HPLC conditions: IC-H column, Hexane:i-PrOH=85:15, flow rate 1.5mL / min, column temperature 25℃, detection wavelength 254nm, t major =34.567min,t minor =44.746min. Optical rotation:[α] D 25 =+87.4(c=0.88,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ7.40(d,J=8.4Hz,2H),7.05(d,J=8.0Hz,2H),6.80-6.69(m,2H),6.67(s,1H),6.55(s,1H),5.18(dd,J=8.0,6.0Hz,1H),3.92(m,1H),3.8 2(s,3H),3.81(s,3H),3.76(s,3H),3.50-3.62(m,1H),3.14-3.05(m, 2H),2.73-2.85(m,1H),2.53-2.64(m,1H),2.33(s,3H),2.28(s,3H). 13 C NMR (100 MHz, CDCl 3)δ168.8,152.3,149.8,146.3,142.9,137.9,137.1,131.7,129.7,129.2,128.0,127.0,126.7 ,121.2,120.7,112.3,110.9,60.4,55.9,55.8,55.3,42.9,38.7,27.1,21.4,20.6.IR(neat):ν max =2962,1763,1596,1511,1488,1261,1155,1032cm -1 .HRMS(m / z):[M+H] + calculated for C 28 H 31 79 BrNO 7 S + ,604.0999;found,604.1004;C 28 H 31 81 BrNO 7 S + ,606.0979;found,606.0984.

[0120] In Example 48, R 2 is Bz, X is bromine, and R 11 For example, compound 15cd was synthesized when R is Me and R is Ts group. The ligand used was (1R,2R)-(+)-Np-toluenesulfonyl-1,2-diphenylethylenediamine. The total yield of the three steps was 84%, and ee=94%(S). HPLC conditions: AD-H column, Hexane: i-PrOH=80:20, flow rate 1.0mL / min, column temperature 25℃, detection wavelength 254nm, t major =15.023min,t minor =18.524min. Optical rotation:[α] D 25 =+120.5(c=0.64,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3)δ8.21-8.15(m,2H),7.67-7.60(m,1H),7.54-7.40(m,4H),7.10-7.03(m,2H),,6. 79(d,J=9.2Hz,1H),6.77(s,1H,overlap),6.73(d,J=8.4Hz,1H),6.61(s,1H),5.21 (t,J=7.6Hz,1H),4.04-3.89(m,1H),3.83(s,3H),3.81(s,3H),3.75(s,3H),3.66- 3.54(m,1H),3.19-3.07(m,2H),2.88-2.76(m,1H),2.68-2.59(m,1H),2.34(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ164.6,152.4,150.1,146.3,143.0,138.2,137.2,133.5,131.8,130.2,129.8,129.3,129.3,128.5,128 .1,127.1,126.8,121.4,120.7,112.5,110.9,60.4,55.9,55.9,55.4,42.9,38.8,27.2,21.4.IR(neat):ν max =1738,1511,1487,1450,1261,1213,1154,1025,811,729cm -1 .HRMS(m / z):[M+H] + calculated for C 33 H 33 79 BrNO 7 S + ,666.1156;found,666.1151;C 33 H 33 81 BrNO 7 S + ,668.1135;found,668.1135.

[0121] In Example 49, R 2 is Piv, X is bromine, and R 11For example, compound 15ce was synthesized when R is Me and R is Ts. The ligand used is (1R,2R)-(+)-Np-toluenesulfonyl-1,2-diphenylethylenediamine, and the total yield of the three steps is 82%, with ee=95%(S). HPLC conditions: IC00C3-QG035, H 2 O:MeOH=10:90, flow rate 1.0mL / min, column temperature 25℃, detection wavelength 254nm, t major =16.37min,t minor =18.44min. Optical rotation:[α] D 25 =+104.3(c=0.6,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ7.45-7.41(m,2H),7.06(d,J=8.0Hz,2H),6.78-6.69(m,2H),6.54(s,1H),6.53(s,1H),5.18(t,J=7.2Hz,1H),3.95-3.87(m,1H),3.86(s ,3H),3.83(s,3H),3.73(s,3H),3.62-3.52(m,1H),3.11(d,J=7.6Hz,2H),2.81-2.70(m,1H),2.64-2.54(m,1H),2.33(s,3H),1.33(s,9H). 13 C NMR (100 MHz, CDCl 3 )δ176.5,152.3,150.0,146.3,143.0,138.3,137.3,131.3,129.8,129.3,127.8,127.0,126.8,12 1.2,120.8,112.3,110.9,60.4,55.9,55.9,55.3,42.9,39.0,38.8,27.2,27.1,21.4.IR(neat):ν max =1751,1511,1486,1449,1272,1154,1097,1030,749cm -1 .HRMS(m / z):[M+H] + calculated for C 31 H 37 79 BrNO 7 S +,646.1469;found,646.1469;C 31 H 37 81 BrNO 7 S + ,648.1448;found,648.1457.

[0122] Example 50 Preparation of Compound 17 (Preparation of Intramolecular Oxidative Dearomatization Heck Coupling Reaction Substrate) 11 When is a hydrogen atom, compound 17 is prepared from compound 15 after introducing a protecting group I (PMB) for the hydroxy group. R 2 is TBDPS, X is bromine, and R 11 Take the example where R is a hydrogen atom and R is Ts, compound 17aab is synthesized, and the synthesis route is as follows: [ka] Compound 15aa (10.00 g, 12.71 mmol, 1.0 equiv.), potassium carbonate (5.27 g, 38.13 mmol, 3.0 equiv.) and TBAI (469 mg, 1.27 mmol, 0.1 equiv.) are placed in a reaction bottle, ventilated, protected with argon gas, and dry DMF (180 mL) is added. PMBCl (3.45 mL, 25.42 mmol, 2.0 equiv.) is added to this while stirring at room temperature. The reaction is carried out at room temperature for about 6 hours, and TLC shows that the raw material has completely disappeared. Dimethylamine (1.30 mL, 25.42 mmol, 2.0 equiv.) is added to the reaction solution, stirred at room temperature for 2 hours, and then saturated NH 4The reaction is quenched by adding Cl solution (100 mL). Extract with ethyl acetate (100 mL x 4), combine the organic layers, and wash successively with water (100 mL x 1) and saturated sodium chloride solution (100 mL x 2). Dry the organic layers over anhydrous magnesium sulfate, filter, and concentrate to dryness. The resulting crude product is purified by silica gel column chromatography (petroleum ether / dichloromethane / acetone = 100:100:1, v / v, containing 0.5% aqueous ammonia; silica gel is treated with petroleum ether containing 0.5% aqueous ammonia before being loaded into the column) to obtain white foam solid 16aab (9.9 g, 86% yield). Compound 16aab data: Optical rotation: [α] D 25 =-77.6(c=1.32,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ7.77-7.70(m,4H),7.49(d,J=8.6Hz,2H),7.43-7.25(m,9H),6.96(d,J=8.0Hz,2H),6.93(d, J=8.8Hz,2H),6.70(s,1H),6.52(s,1H),6.31(s,1H),4.93-4.90(m,1H,overlapped),4.90(s,3 H),3.87-3.85(m,1H),3.83(s,3H,overlapped),3.82(s,3H,overlapped),3.57(s,3H),3.48-3 .41(m,1H),2.79-2.76(m,2H),2.56-2.48(m,1H),2.40-2.35(m,1H),2.28(s,3H),1.12(s,9H). 13 C NMR (100 MHz, CDCl 3)δ159.4,152.5,149.5,145.1,143.3,142.6,137.6,135.49,135.47,134.8, 133.4,133.4,130.2,130.1,129.7,129.71,129.69,129.1,127.73,127.68, 127.58,127.56,126.9,126.5,125.6,121.2,118.6,113.6,112.2,110.7,74 .2,55.9,55.53,55.48,55.3,42.8,38.7,26.7,26.2,21.4,19.7.IR(neat):ν max =2932,1513,1485,1463,1428,1248,1155,1033,749cm -1 .HRMS(m / z):[M+H] + calculated for C 49 H 53 79 BrNO 7 SSi + ,906.2490;found,906.2494;C 49 H 53 81 BrNO 7 SSi + ,908.2469;found,908.2481. Compound 16aab (9.00 g, 9.92 mmol, 1.0 equiv.) was dissolved in CH 3 CN / H 2 The mixture was dissolved in 1H2O mixed solvent (210 mL, v / v = 20:1), KF (1.15 g, 19.84 mmol, 2.0 equiv.) was added at room temperature, and the mixture was heated to 50 °C and reacted for about 3 hours. TLC showed that the raw material had completely disappeared. The mixture was cooled to 0 °C and saturated NaHCO 3 The reaction was quenched by the addition of aqueous solution (100 mL) and the mixture was distilled under reduced pressure to CH 3The CN is removed, the residue is extracted with ethyl acetate (100 mL x 3), the organic layers are combined, washed with saturated aqueous sodium chloride solution (100 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (petroleum ether / acetone = 4:1, v / v, containing 0.5% aqueous ammonia; silica gel is treated with petroleum ether containing 0.5% aqueous ammonia before loading onto the column) to give white foamy solid 17aab (6.04 g, 91% yield). Compound 17aab data:Optical rotation:[α] D 25 =-103.2(c=0.6,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ7.48(d,J=8.4Hz,2H),7.39(d,J=8.4Hz,2H),7.03(d,J=8.0Hz,2H),6.92-6.90(m,2H),6.82(d,J=8.4Hz, 1H),6.74(d,J=8.4Hz,1H),6.64(s,1H),6.45(s,1H),5.46(s,1H),5.12(dd,J=9.6,4.8Hz,1H),4.92(s,2H) ,3.93-3.88(m,1H),3.85(s,2H),3.82(s,3H,overlapped),3.82(s,3H,overlapped),3.61-3.53(m,1H),3. 17(dd,J=14.0,4.8Hz,1H),3.05(dd,J=14.0,9.6Hz,1H),2.80-2.71(m,1H),2.57-2.51(m,1H),2.30(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ159.6,152.7,145.8,145.4,143.9,143.0,137.3,130.3,129.3,128.8,127.2,126.8, 124.8,121.5,113.8,112.9,110.9,74.4,56.0,55.4,43.1,39.2,26.9,21.6.IR(neat):ν max =1596,1512,1484,1462,1441,1245,1151,1029,748cm -1.HRMS (m / z):[M+H] + calculated for C 33 H 35 79 BrNO 7 S + ,668.1312;found,668.1313;C 33 H 35 81 BrNO 7 S + ,670.1292;found,670.1298.

[0123] Example 51 Preparation of Compound 17 (Preparation of Intramolecular Oxidative Dearomatization Heck Coupling Reaction Substrate) 11 When is a hydrogen atom, compound 17 is prepared from compound 15 after introducing a protecting group I(Bn) for the hydroxy group. [ka] R 2 is TBDPS, X is bromine, and R 11 For example, compound 17aaa is synthesized when R is hydrogen atom and R is Ts. The synthetic route is shown in Example 48. Compound 17aaa data: 1 H NMR (400 MHz, CDCl 3 )δ7.57(d,J=7.2Hz,2H),7.41-7.37(m,4H),7.34-7.31(m,1H),7.03(d,J=8.0Hz,2H),6.84(d,J= 8.4Hz,1H),6.75(d,J=8.4Hz,1H),6.65(s,1H),6.45(s,1H),5.47(s,1H),5.13(dd,J=9.6,4.8Hz ,1H),4.98(s,2H),3.94-3.89(m,1H),3.85(s,3H),3.82(s,3H),3.61-3.54(m,1H),3.17(dd,J=1 4.0,5.2Hz,1H),3.05(dd,J=14.0,9.6Hz,1H),2.79-2.71(m,1H),2.57-2.51(m,1H),2.30(s,3H). 13 C NMR (100 MHz, CDCl3 )δ152.7,145.8,145.3,143.9,143.0,137.6,137.3,130.3,129.3,128.7,128.5,128.4,128.0,1 27.2,126.8,124.8,121.4,112.9,111.0,110.8,74.6,56.0,43.1,39.2,26.9,21.6.IR(neat):ν max =1511,1484,1454,1271,1150,1028,750cm -1 .HRMS(m / z):[M+H] + calculated for C 32 H 33 BrNO 6 S + ,638.1206;found,638.1211;C 33 H 35 81 BrNO 7 S + ,640.1186;found,640.1196.

[0124] Example 52 Preparation of Compound 17 (Preparation of Intramolecular Oxidative Dearomatization Heck Coupling Reaction Substrate) 11 When is a protecting group I for a hydroxy group, compound 17 is directly prepared from compound 15 above. R 2 is Ac, X is bromine, and R 11 Take the example where R is Me and R is Ts, compound 17aac is synthesized, and the synthesis route is as follows: [ka] Compound (S)-15cc (1.00g, 1.65mmol, 1.0 equiv.) was dissolved in MeOH (10mL) and K 2 CO 3(0.57g, 4.13mmol, 2.5equiv.) is added at room temperature and reacted with stirring for 0.5 hours, TLC shows that the raw material has completely disappeared. Cool to 0℃, add water to quench the reaction, extract with ethyl acetate (20mL x 3), combine the organic layers, dry over anhydrous magnesium sulfate, filter, and concentrate under reduced pressure. Purify the crude product by silica gel column chromatography (petroleum ether / acetone = 6:1, v / v) to obtain a white foamy solid (S)-17aac (854mg, 92% yield). Optical rotation: [α] D 25 =+83.7(c=0.84,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ7.39(d,J=8.0Hz,2H),7.02(d,J=8.0Hz,2H),6.83(d,J=8.4Hz,1H),6.73(d,J=8. 8Hz,1H),6.66(s,1H),6.45(s,1H),5.48(s,1H),5.12(dd,J=10.0,4.8Hz,1H),3.94- 3.89(m,1H),3.86(s,3H),3.82(s,6H),3.61-3.54(m,1H),3.16(dd,J=14.0,4.8Hz,1 H),3.04(dd,J=14.0,9.6Hz,1H),2.79-2.70(m,1H),2.57-2.51(m,1H),2.32(s,3H). 13 C NMR (100 MHz, CDCl 3 )δ152.5,146.5,145.8,144.0,143.0,137.4,130.2,129.3,128.8,127.2,1 26.7,124.8,121.0,112.9,111.0,56.0,43.0,39.2,26.9,21.6.IR(neat):ν max =3428,1512,1487,1449,1265,1149,1031cm -1 .HRMS(m / z):[M+H] + calculated for C 26 H 29 79 BrNO 6 S +,562.0893;found,562.0893;C 33 H 35 81 BrNO 7 S + ,564.0873;found,564.0873.

[0125] Example 53 Preparation of Compound 17 (Preparation of Intramolecular Oxidative Dearomatization Heck Coupling Reaction Substrate) 11 When is a protecting group I for a hydroxy group, compound 17 is directly prepared from compound 15 above. R 2 is TBDPS, X is bromine, and R 11 Take the example where R is Me and R is Ts, compound 17aac is synthesized, and the synthesis route is as follows: [ka] Compound (R)-15ba (10.00 g, 12.49 mmol, 1.0 equiv.) was dissolved in CH 3 CN / H 2 The mixture was dissolved in 1H2O mixed solvent (210 mL, v / v = 20:1), KF (1.45 g, 24.97 mmol, 2.0 equiv.) was added at room temperature, and the mixture was heated to 50 °C and reacted for about 3 hours. TLC showed that the raw materials had completely disappeared. The mixture was cooled to 0 °C and saturated NaHCO 3 The reaction was quenched by the addition of aqueous solution (100 mL) and the mixture was distilled under reduced pressure to CH 3 The CN is removed, the residue is extracted with ethyl acetate (100 mL x 3), the organic layers are combined, washed with saturated aqueous sodium chloride solution (100 mL x 2), dried over anhydrous magnesium sulfate, filtered, and concentrated under reduced pressure. The crude product is purified by silica gel column chromatography (petroleum ether / acetone = 4:1, v / v) to obtain a white foamy solid (R)-17aac (6.67 g, 95% yield). Optical rotation: [α] D 25 =-96.9(c=0.8,CHCl 3 ).

[0126] Example 54 Preparation of compound 18 (intramolecular oxidative dearomatization Heck reaction). X is bromine and R 1 Take the example where R is Me and R is Ts, compound 18aac is synthesized, and the synthesis route is as follows: [ka] Compound 17aac (200 mg, 0.356 mmol, 1.0 equiv.), palladium chloride (6.3 mg, 0.0356 mmol, 0.1 equiv.), phosphine ligand (16.8 mg, 0.0356 mmol, 0.1 equiv.) and potassium carbonate (147 mg, 1.067 mmol, 3.0 equiv.) are placed in a reaction vessel, evacuated, protected with argon gas, degassed dry DMF (4 mL, c = 0.1 mol / L) is added, and the reaction is carried out in an oil bath at 80 ° C for 12 hours. The raw material is observed by TLC, the reaction solution is cooled to room temperature, and the reaction is quenched by adding water (4 mL) at 0 ° C, extracted with ethyl acetate (5 mL × 3), the organic layers are combined, and washed successively with water (10 mL × 1) and saturated sodium chloride solution (10 mL × 1). The organic layer was dried over anhydrous magnesium sulfate, filtered, and concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether / dichloromethane / acetone = 15:15:1, v / v) to obtain a white foamy solid 18aac (27 mg, 16% yield). 18aac data: Optical rotation: [α] D 25 =+4.5(c=0.4,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3)δ7.66(d,J=8.4Hz,2H),7.27(d,J=4.0Hz,2H),7.16(s,1H),6.84-6.77(m, 2H),6.22(s,1H),4.95(d,J=3.6Hz,1H),3.92(s,3H),3.86(s,3H),3.74(s,3 H),3.73-3.68(m,1H),3.28(dd,J=17.6,4.8Hz,1H),3.20(dd,J=17.6,1.6Hz ,1H),3.04-2.96(m,1H),2.41(s,3H),2.22-2.19(m,1H),1.40-1.26(m,1H). 13 C NMR (100 MHz, CDCl 3 )δ180.8,157.9,152.2,151.3,147.4,143.9,137.2,130.3,130.0,127.8,127. 1,124.0,122.4,120.0,112.3,56.0,55.0,43.6,40.3,39.0,21.7.IR(neat):ν max =2936,1674,1649,1616,1483,1280,1213,1159cm -1 .HRMS(m / z):[M+H] + calculated for C 26 H 28 NO 6 S + ,482.1632;found,482.1636.

[0127] Examples 55-58 Preparation of compound 18 (solvent screening of the intramolecular oxidative dearomatization Heck reaction). X is bromine and R 1 Take the example where R is Me and R is Ts, compound 18aac is synthesized, and the synthesis route is as follows: [ka] The synthesis steps of compound 18aac in Examples 55-58 are all the same as in Example 54, and the conditions such as the reagents for synthesis and the amounts used are all as shown in the synthesis route. The examples in each group are distinguished as follows: different solvents and temperatures were used in the reaction to prepare compound 18aac from compound 17aac. The results are shown in the following table: [Table 6] JPEG0007604038000071.jpg67170

[0128] Examples 59-62 Preparation of compound 18 (temperature screening of intramolecular oxidative dearomatization Heck reaction). X is bromine and R 1 Take the example where R is Me and R is Ts, compound 18aac is synthesized, and the synthesis route is as follows: [ka] The synthesis procedures for compound 18aac in Examples 59 to 62 are all the same as those in Example 58, and the conditions such as the reagents and their amounts used in the synthesis are all as shown in the synthesis route. The differences from Example 58 are as follows: in the reaction for preparing compound 18aac from compound 17aac, a different reaction temperature is used. [Table 7] JPEG0007604038000073.jpg67170

[0129] Examples 63 to 67 Preparation of compound 18 (base screening of intramolecular oxidative dearomatization Heck reaction). X is bromine and R 1 Take the example where R is Me and R is Ts, compound 18aac is synthesized, and the synthesis route is as follows: [ka] The synthesis procedures for compound 18aac in Examples 63-67 are all the same as those in Example 62, and the conditions such as the reagents and their amounts used in the synthesis, reaction temperature, etc. are all as shown in the synthesis route. The only difference between the examples in each group is that different bases were used in the reaction to prepare compound 18aac from compound 17aac. The results are shown in the following table: [Table 8] JPEG0007604038000075.jpg82170

[0130] Examples 68-69 Preparation of compound 18 (selection of catalyst and ligand equivalent number for intramolecular oxidative dearomatization Heck reaction). X is bromine and R 1 Take the example where R is Me and R is Ts, compound 18aac is synthesized, and the synthesis route is as follows: [ka] The synthesis procedures for compound 18aac in Examples 68-69 are all the same as those in Example 62, and the conditions such as the reagents and their amounts used in the synthesis, reaction temperature, etc. are all as shown in the synthesis route. The only difference between the examples in each group is the equivalent amount of palladium chloride and ligand used in the reaction to prepare compound 18aac from compound 17aac. The results are shown in the following table: [Table 9] JPEG0007604038000077.jpg40170

[0131] Examples 70-74 Preparation of compound 18 (screening of the intramolecular oxidative dearomatization Heck reaction). X is bromine and R 1 Take the example where R is Me and R is Ts, compound 18aac is synthesized, and the synthesis route is as follows: [ka] The synthesis procedures for compound 18aac in Examples 70-74 are all the same as those in Example 62, and the conditions such as the reagents and their amounts used in the synthesis, reaction temperature, etc. are all as shown in the synthesis route. The only difference between the examples in each group is the concentration of the reaction for preparing compound 18aac from compound 17aac. The results are as shown in the following table: [Table 10] JPEG0007604038000079.jpg80170

[0132] Example 75 Preparation of compound 18 (a preferred application of the intramolecular oxidative dearomatization Heck reaction). [ka] The synthesis procedure of compound 18aac in Example 75 is the same as that in Example 67, and the conditions such as the reagents used in the synthesis, the amounts used, and the reaction temperature are all as shown in the synthesis route. The only difference from Example 67 is that the reaction concentration for preparing compound 18aac from compound 17aac is different. The results are as shown in the following table: [Table 11] JPEG0007604038000081.jpg24170

[0133] Examples 76-87 Preparation of compound 18 (ligand selection for intramolecular oxidative dearomatization Heck reaction). X is bromine and R 1 Take the example where R is Me and R is Ts, compound 18aac is synthesized, and the synthesis route is as follows: [ka] The synthesis procedures for compound 18aac in Examples 76-87 are all the same as those in Example 75, the base used is potassium phosphate, and the conditions such as the reagents and their amounts used in the synthesis, and the reaction temperature are all as shown in the synthesis route. The only difference between the examples in each group is the ligand used in the reaction to prepare compound 18aac from compound 17aac. The results are shown in the following table: [Table 12] JPEG0007604038000083.jpg169170

[0134] Examples 88-97 Preparation of compound 18 (screening the ratio of metal catalyst and ligand usage in the intramolecular oxidative dearomatization Heck reaction). X is bromine and R 1 Take the example where R is Me and R is Ts, compound 18aac is synthesized, and the synthesis route is as follows: [ka] The synthesis procedures for compound 18aac in Examples 88-97 are all the same as those in Example 75, and the conditions such as the reagents and their amounts used in the synthesis, and the reaction temperature are all as shown in the synthesis route. The only difference between the examples in each group is the amount of palladium chloride and ligand used in the reaction to prepare compound 18aac from compound 17aac. The results are shown in the following table: [Table 13] JPEG0007604038000085.jpg151170

[0135] Examples 98-100 Preparation of compound 18 (selection of the ratio of the preferred ligand and metal catalyst used in the intramolecular oxidative dearomatization Heck reaction). X is bromine and R 1 Take the example where R is Me and R is Ts, compound 18aac is synthesized, and the synthesis route is as follows: [ka] The synthesis procedures for compound 18aac in Examples 98-100 are all the same as those in Example 81, and the conditions such as the reagents and their amounts used in the synthesis, and the reaction temperature are all as shown in the synthesis route. The only difference between the examples in each group is the amount of palladium chloride and ligand used in the reaction to prepare compound 18aac from compound 17aac. The results are shown in the following table: [Table 14] JPEG0007604038000087.jpg54170

[0136] Examples 101-102 Preparation of compound 18 (selection of the ratio of the preferred ligand and metal catalyst used in the intramolecular oxidative dearomatization Heck reaction). X is bromine and R 1 Take the example where R is Me and R is Ts, compound 18aac is synthesized, and the synthesis route is as follows: [ka] The synthesis procedures for compound 18aac in Examples 101-102 are the same as those in Example 83, and the conditions such as the reagents and their amounts used in the synthesis, and the reaction temperature are all as shown in the synthesis route. The only difference between the examples in each group is the amount of ligand used in the reaction to prepare compound 18aac from compound 17aac. The results are shown in the following table: [Table 15] JPEG0007604038000089.jpg39170

[0137] Examples 103-104 Preparation of compound 18 (selection of the ratio of the preferred ligand and metal catalyst used in the intramolecular oxidative dearomatization Heck reaction). X is bromine and R 1 Take the example where R is Me and R is Ts, compound 18aac is synthesized, and the synthesis route is as follows: [ka] The synthesis procedures for compound 18aac in Examples 103-104 are all the same as those in Example 84, and the conditions such as the reagents and their amounts used in the synthesis, and the reaction temperature are all as shown in the synthesis route. The only difference between the examples in each group is the amount of ligand used in the reaction to prepare compound 18aac from compound 17aac. The results are shown in the following table: [Table 16] JPEG0007604038000091.jpg40170

[0138] Examples 105-106 Preparation of compound 18 (use of favorable ratios of ligand and metal catalyst loadings in the intramolecular oxidative dearomatization Heck reaction). X is bromine and R 1 Take the example where R is Me and R is Ts, compound 18aac is synthesized, and the synthesis route is as follows: [ka] The synthesis procedures for compound 18aac in Examples 105-106 are all the same as those in Example 89, and the conditions such as the reagents and their amounts used in the synthesis, and the reaction temperature are all as shown in the synthesis route. The only difference between the examples in each group is the ligand used in the reaction to prepare compound 18aac from compound 17aac. The results are shown in the following table: [Table 17] JPEG0007604038000093.jpg31170

[0139] Example 107 Purification of compound 18aac. The product (R)-18aac of the above Examples 54-106 was recrystallized with ethanol, and the recrystallization yield was 80%, and the product ee value was improved to 99.9% (R). Mp: 162-164℃. Optical rotation: [α] D 25 =+11.9(c=0.52,CHCl 3HPLC conditions: AD-H column, Hexane: i-PrOH = 60:40, flow rate 1 mL / min, column temperature 25°C, detection wavelength 254 nm, t major =16.632min, t minor =9.754min. (S)-18aac was recrystallized from isopropanol, the recrystallization yield was 93%, the product ee value was improved to 99.9(S), Mp: 162-164℃. Optical rotation: [α] D 25 =-11.3(c=0.68,CHCl 3 HPLC conditions: AD-H column, Hexane: i-PrOH = 60:40, flow rate 1 mL / min, column temperature 25°C, detection wavelength 254 nm, t major =9.888min,t minor =16.453min.

[0140] Example 108 Preparation of compound 18. X is bromine and R 1 Take the example where R is PMB and R is Ts, compound 18aab is synthesized, and the synthesis route is as follows: [ka] Compound 17aab (4.00 g, 5.98 mmol, 1.0 equiv.), palladium chloride (106 mg, 0.598 mmol, 0.1 equiv.), phosphine ligand (847 mg, 1.794 mmol, 0.3 equiv.) and potassium phosphate (3.81 g, 17.94 mmol, 3.0 equiv.) are placed in a reaction vessel, evacuated, protected with argon gas, degassed dry DMF (80 mL, c = 0.075 mol / L) is added to it, and the vessel is reacted for 40 min in an oil bath at 145 ° C. Observe the raw material by TLC, cool the reaction solution to room temperature, add water (40 mL) at 0 ° C to quench the reaction, extract with ethyl acetate (60 mL × 3), combine the organic layers, and wash with water (50 mL × 1) and saturated sodium chloride solution (50 mL × 1) in sequence. The organic layer is dried over anhydrous magnesium sulfate, filtered, concentrated, and the resulting crude product is purified by silica gel column chromatography (petroleum ether / dichloromethane / acetone=15:15:1, v / v) to obtain a white foamy solid 18aab (2.07 g, 72% yield). 18aab data: Optical rotation: [α] D 25 =+57.1(c=0.8,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ7.65(d,J=8.0Hz,2H),7.37(d,J=8.4Hz,2H),7.26(d,J=8.4Hz,2H),7.20(s,1 H),6.92-6.79(m,4H),6.17(s,1H),5.26(d,J=11.2Hz,1H),4.94-4.92(m,2H),3. 88(s,3H),3.82(s,3H),3.69(dd,J=13.6,3.6Hz,1H),3.40(s,3H),3.31-3.19(m ,2H),3.06-2.99(m,1H),2.40(s,3H),2.14(d,J=12.8Hz,1H),1.33-1.25(m,1H). 13 C NMR (100 MHz, CDCl 3)δ180.8,159.6,157.7,152.0,151.2,146.3,143.9,137.2,130.3,130.0,129.5,129.1,128.0,127 .1,124.0,122.4,120.3,114.1,112.4,74.2,56.0,55.4,54.9,43.6,40.3,39.2,21.6.IR(neat):ν max =1673,1648,1613,1513,1480,1277,1248,1215,1202,1157,718cm -1 .HRMS(m / z):[M+H] + calculated for C 33 H 34 NO 7 S + ,588.2050;found,588.2051.

[0141] Examples 109-110 Preparation of compound 18. X is bromine and R 1 Take the example where R is PMB and R is Ts, compound 18aab is synthesized, and the synthesis route is as follows: [ka] The synthesis procedures for compound 18aab in Examples 109-110 are all similar to those in Example 108, and the conditions such as the reagents and their amounts used in the synthesis, and the reaction temperature are all as shown in the synthesis route. The only difference between the examples in each group is that the ligands used in the reaction to prepare compound 18aac from compound 17aac are different. The results are shown in the following table: [Table 18] JPEG0007604038000096.jpg37170

[0142] Example 111 Preparation of compound 18. X is bromine and R 1 Take the compound 18aaa as an example, where R is Bn and R is Ts, and the synthesis route is as follows: [ka] The synthesis procedure of 18aaa was the same as in Example 83, and the conditions such as the reagents and their amounts used in the synthesis, and the reaction temperature are all as shown in the synthesis route. 1 H NMR (400 MHz, CDCl 3 )δ7.65(d,J=8.4Hz,2H),7.46-7.45(m,2H),7.41-7.32(m,3H),7.25(d,J=8.0Hz,2H),7.15(s,1H),6 .88-6.81(m,2H),6.18(s,1H),5.30(s,1H,overlapped),5.28(d,J=12.4Hz,1H,overlapped),5.07( d,J=11.6Hz,1H),4.93(d,J=3.6Hz,1H),3.87(s,3H),3.69(dd,J=14.0,4.0Hz,1H),3.34(s,3H),3.2 8-3.20(m,1H),3.07-3.00(m,1H),2.40(s,3H),2.16(d,J=12.4Hz,1H),1.31(dd,J=13.2,5.2Hz,1H). 13 C NMR (100 MHz, CDCl 3 )δ180.8,157.7,152.1,151.3,146.2,143.9,137.5,137.2,130.4,123.0,128.8,128.2,128.1, 127.3,127.1,124.2,122.5,120.1,112.5,74.3,56.0,54.9,43.7,40.3,39.2,21.7.IR(neat):ν max =1673,1647,1615,1480,1433,1278,1215,1158,747cm -1 .IR(neat):ν max =1673,1647,1615,1480,1433,1278,1215,1158,747cm -1 .HRMS(m / z):[M+H] + calculated for C 32 H 32 NO 6 S + ,558.1945;found,558.1940.

[0143] Example 112 Preparation of compound 19. R 1 Take the example where R is PMB and R is Ts, compound 19 is synthesized, and the synthesis route is as follows: [ka] Compound 18aab (100.0 mg, 0.170 mmol, 1.0 equiv.) was dissolved in CH 2 Cl 2 (4mL), -40 o C, trifluoroacetic acid (65uL, 0.851mmol, 5.0equiv.) was added, and the mixture was reacted for 17 hours. o The temperature was raised to 0°C and the reaction was continued for 7 hours, after which TLC showed that the raw materials had completely disappeared. 3 The reaction was quenched by adding aqueous solution (2 mL) and CH 2 Cl 2 (5 mL × 3), the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated, and the resulting crude product was purified by silica gel column chromatography (petroleum ether / acetone = 3:1, v / v) to give white foamy solid 19 (56.0 mg, 70% yield). Optical rotation: [α] D 25 =+13.8(c=1.44,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ7.67(d,J=8.2Hz,2H),7.45(s,1H),7.28(s,1H),6.76(d,J=8.4Hz,1H),6.60(d ,J=8.4Hz,1H),6.23(d,J=15.6Hz,2H),4.96(d,J=3.3Hz,1H),3.89(s,3H),3.74- 3.71(m,1H,overlapped),3.71(s,3H),3.30-3.18(m,2H),3.03(td,J=13.2,3.2H z,1H),2.41(s,3H),2.41-2.36(m,1H,overlapped),1.31(td,J=12.8,4.8Hz,1H). 13C NMR (100 MHz, CDCl 3 )δ180.9,157.8,151.3,145.7,143.9,143.5,137.3,129.9,128.2,127.1, 122.5,119.7,110.0,56.4,55.0,43.4,40.5,38.9,37.6,21.7.IR(neat):ν max =3350,2929,1670,1640,1484,1219,1158,1054cm -1 .HRMS (m / z):[M+H] + calculated for C 25 H 26 NO 6 S + ,468.1475;found,468.1477.

[0144] Example 113 Preparation of compound 19. R 1 Take the example where R is PMB and R is Ts, compound 19 is synthesized, and the synthesis route is as follows: [ka] Compound 18aab (200.0 mg, 0.34 mmol, 1.0 equiv.) is dissolved in DMF (3.5 mL), and hydrobromic acid (48% aqueous solution, 0.7 mL) is added dropwise at room temperature. After the addition, the temperature is raised to 45°C and the reaction is continued for 20 hours. The reaction solution is then cooled to room temperature, hydrobromic acid (48% aqueous solution, 0.3 mL) is added, and after the addition, the temperature is further raised to 45°C and the reaction is continued for 15 hours. The reaction solution is again cooled to room temperature, hydrobromic acid (48% aqueous solution, 0.3 mL) is added, and after the addition, the temperature is further raised to 45°C and the reaction is continued for 5 hours, and TLC shows that the raw material has completely disappeared. Saturated NaHCO 3Add aqueous solution until gas is no longer generated, extract with ethyl acetate (8mL x 3), combine organic layers, wash with water (5mL x 1) and saturated sodium chloride (5mL x 1) in that order, dry organic layers over anhydrous magnesium sulfate, filter, and concentrate. Purify the obtained crude product by silica gel column chromatography (petroleum ether / acetone = 4:1, v / v) to obtain white foamy solid 19 (137mg, yield 86%). Hydrogen spectrum data is the same as in Example 112.

[0145] Example 114 Preparation of compound 19. R 1 Take the example where R is Me and R is Ts, compound 19 is synthesized, and the synthesis route is as follows: [ka] Compound 18aac (100.0 mg, 0.208 mmol, 1.0 equiv.) was dissolved in dry N,N-dimethylacetamide (DMAc, 7 mL), sodium hydrogen sulfide (purity 68%-72%, 66.4 mg, 0.83 mmol, 4.0 equiv.) was added, and the mixture was reacted at 125 °C for 1 h, and TLC showed that the raw material was completely consumed. The mixture was cooled to 0 °C, and the reaction was quenched by adding 0.5 M aqueous HCl, extracted with ethyl acetate (5 mL × 4), and the organic layers were combined and washed with water (5 mL × 2), saturated NaHCO 3 The organic layer was dried over anhydrous magnesium sulfate, filtered, concentrated, and the crude product was purified by silica gel column chromatography (petroleum ether / acetone=4:1, v / v) to obtain white foamy solid 19 (69.0 mg, 71% yield). Hydrogen spectrum data is the same as in Example 112.

[0146] Example 115 Preparation of intermediate I. Take R as an example, compound 21 (i.e. intermediate I) is synthesized, and the synthesis route is as follows: [ka] Compound 19 (510.0 mg, 1.09 mmol, 1.0 equiv.) was dissolved in CH 2 Cl 2 / MeOH mixed solution (v / v=1:1, 10 mL), o Cool to room temperature and add NaBH 4 (82.5 mg, 2.18 mmol, 2.0 equiv.) is slowly added, and the reaction solution is then warmed to room temperature. After reacting for about 15 minutes, the complete disappearance of the raw material is detected by TLC. o Cool to C, add water to quench the reaction, separate the organic layer, extract the aqueous layer with dichloromethane (10 mL x 3), combine the organic layers, wash with saturated NaCl solution (10 mL x 1), dry over anhydrous magnesium sulfate, filter and concentrate to obtain the crude product of compound 20 as a white foam, which is used for the next reaction directly without purification. Under the protection of argon gas, the crude product of compound 20 is placed in a reaction bottle, ventilated, protected with argon gas, N,N-dimethylformamide dimethyl acetal (2.5 mL) is added, heated to 60 °C and reacted for about 40 minutes, TLC observation shows that the reaction of the raw materials is complete. The reaction liquid is decompressed to remove the solvent, and the obtained crude product is separated and purified by silica gel column chromatography (petroleum ether / ethyl acetate, v / v = 5: 1 to 3.5: 1) to obtain a white foamy solid 21 (418 mg, two-step yield 85%). Optical rotation: [α] D 25 =-117.8(c=0.72,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3)δ7.73(d,J=8.0,2H),7.30(d,J=8.0Hz,2H),6.64(d,J=8.0Hz,1H),6.51(d,J=8.0Hz,1H) ,5.60(d,J=6.4Hz,1H),5.19(s,1H),4.98(dd,J=13.6,6.4Hz,2H),3.82(s,3H),3.74(dd, J=12.0,5.2Hz,1H),3.59(s,3H),3.26(td,J=13.2,3.6Hz,1H),3.00(dd,J=18.2,6.8Hz,1 H),2.89(d,J=18.0Hz,1H),2.44(s,3H),1.95(td,J=12.8,5.4Hz,1H),1.74-1.70(m,1H). 13 C NMR (100 MHz, CDCl 3 )δ153.0,144.8,143.4,143.1,137.3,132.1,129.7,129.0,127.4,126.1,119.5,11 3.2,112.5,95.4,88.6,56.4,55.0,54.4,45.9,38.9,37.1,36.0,21.6.IR(neat):ν max =2922,1603,1502,1234,1155,725cm -1 .HRMS(m / z):[M+H] + calculated for C 25 H 26 NO 5 S + ,452.1526;found,452.1519.

[0147] Example 116 Preparation of compound 22. Take R as an example, compound 22 is synthesized by the following synthesis route: [ka] The reaction bottle was ventilated and protected with argon gas, dibutyl ether (2.0 mL) was added, 48% aqueous HBr (94 uL, 0.555 mmol, 5.0 equiv.) was cooled to -20 °C, and compound 21 (50.0 mg, 0.111 mmol, 1.0 equiv.) was dissolved in dry CH 2Cl 2 (2.0 mL) solution is added dropwise. After the addition is complete, the mixture is reacted at -20°C for 20 hours, then the temperature is raised to -10°C and the mixture is reacted for about 10 hours. The complete disappearance of the raw material is observed by TLC. 3 The reaction was quenched by adding aqueous solution (5 mL), extracted with dichloromethane (5 mL × 4), the organic layers were combined, dried over anhydrous magnesium sulfate, filtered, and concentrated, and the obtained crude product was separated and purified by silica gel column chromatography (petroleum ether / dichloromethane / acetone, v / v / v = 15:15:1 to 10:10:1) to obtain white foamy solid 22 (46 mg, yield 95%). Optical rotation: [α] D 25 =-149.0(c=0.52,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ7.74(d,J=8.0Hz,2H),7.34(d,J=8.0Hz,2H),6.66(d,J=4Hz,1H),6.58(dd,J=8.0,2.0Hz ,1H),6.50(d,J=8.0Hz,1H),6.10(dd,J=10.0,2.8Hz,1H),4.72-4.78(m,1H),4.65(s,1H),3 .83(s,3H),3.82-3.73(m,1H),3.09(q,J=2.8Hz,1H),2.96-2.85(td,J=12.4,4,1H),2.74- 2.59(m,2H),2.45(s,3H),1.98(td,J=12.4,5.2Hz,1H),1.89(ddd,J=12.8,4.0,1.6Hz,1H). 13 C NMR (100 MHz, CDCl 3 )δ193.6,146.5,144.9,143.7,142.9,137.3,133.3,130.0,127.6,127.1,124.2 ,120.4,115.3,87.7,56.8,52.4,43.4,40.8,39.3,33.4,28.1,21.6.IR(neat):ν max =2923,2852,1676,1505,1442,1278,1158cm -1 .HRMS(m / z):[M+H] +calculated for C 24 H 24 NO 5 S + ,438.1370;found,438.1362.

[0148] Example 117 Preparation of compound 24 (codeine). The synthetic route to compound 24 (codeine) is as follows: [ka] Compound 22 (10.0 mg, 0.023 mmol, 1.0 equiv.) was placed in a reaction bottle, ventilated, and protected with argon gas. Dry tetrahydrofuran (1.0 mL) was added, and 0 o Cool to 0°C, add lithium aluminum hydride (1M tetrahydrofuran solution, 0.115mmol, 5.0 equiv.), and after the addition is complete, warm to room temperature and react. After about 10 hours, TLC is used to detect that the raw materials have completely reacted. o Cool to 30°C, add isopropanol (35uL), stir for 5 minutes, add water (5uL), stir for 5 minutes, add 15% aqueous sodium hydroxide (5uL) and water (15uL) in sequence, warm the reaction to room temperature, and continue stirring for 30 minutes. Filter the resulting mixture through Celite, wash the filter cake with dichloromethane, and concentrate the filtrate under reduced pressure to obtain crude compound 23. Use directly in the next reaction without separation and purification. The crude product 23 was dissolved in methanol (1.0 mL), and paraformaldehyde (11.0 mg, 0.115 mmol, 5.0 equiv.) was added. The mixture was stirred at room temperature for 1.5 hours. After that, it was detected by LC-MS that the raw material had completely disappeared. o The reaction is cooled to 0° C., sodium borohydride (6.0 mg, 0.14 mmol, 6.0 equiv.) is added, and the reaction is then warmed to room temperature and reacted for 20 min, after which TLC and LC-MS show the reaction is complete. oCool to 30°C, quench by adding saturated aqueous ammonium chloride, dilute the reaction solution by adding dichloromethane (1.0 mL), adjust the aqueous layer to pH = 10 with 15% aqueous sodium hydroxide, separate the organic layer, extract the aqueous layer with dichloromethane (3 mL x 4), combine the organic layers, dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The obtained crude product is separated and purified by silica gel column chromatography (gradient elution from dichloromethane / methanol v / v = 20:1 to 8:1) to obtain white solid 24 (6.0 mg, yield 85%). Optical rotation: [α] D 25 =-131.0(c=0.3,EtOH). 1 H NMR (400 MHz, CDCl 3 )δ6.66(d,J=8.0Hz,1H),6.57(d,J=8.0Hz,1H),5.71(d,J=10,0Hz,1H),5.29(dt,J=10.0,2.8 Hz,1H),4.89(d,J=6.4Hz,1H),4.21-4.15(m,1H),3.84(s,3H),3.37(dd,J=6.4,3.2Hz,1H),3 .05(d,J=18.8Hz,1H),2.76-2.66(m,1H),2.62(dd,J=12.4,5.2Hz,1H),2.46(s,3H),2.44-2. 37(m,1H),2.32(dd,J=18.4,6.0Hz,1H),2.09(td,J=12.4,5.2Hz,1H),1.88(d,J=12.4Hz,1H). 13 C NMR (100 MHz, CDCl 3 )δ146.3,142.2,133.5,131.0,128.1,127.0,119.6,112.9,91.3,66.3,58.9,56.3,46.5,43.0,42.9,40.6,35.6,20.5.IR(neat):ν max =3370,2929,2843,1635,1502,1452,1274,1265,1205,1120,1054,731cm -1 .HRMS(m / z):[M+H] + calculated for C 18 H 22 NO 3 +,300.1594;found,300.1587.

[0149] Example 118 Preparation of compound 26. Take R as an example, compound 26 is synthesized, and the synthesis route is as follows: [ka] The compound 21 (50.0 mg, 0.11 mmol, 1.0 equiv.) and tetraphenylporphyrin (14.0 mg, 0.022 mmol, 0.2 equiv.) are dissolved in dichloromethane (2 mL), and reacted at room temperature for 1 hour under irradiation of blue LED light (40 w, Kessil (registered trademark)) by bubbling with oxygen gas, and TLC is used to detect the complete disappearance of the raw material. The reaction solution is degassed for 30 minutes by ultrasonication with argon gas flowing through it, and residual oxygen in the solution is eliminated. Isopropanol / formic acid / water (v / v / v=1:1:1, 1.5 mL) and 10% palladium carbon (15 mg, 30% wt.) are added to the reaction solution, and the reaction is carried out at room temperature for 12 hours at a hydrogen pressure of 10 atm in a high-pressure hydrogenation furnace, and TLC detection shows that the reaction is complete. The reaction mixture is filtered through Celite, the filter cake is washed three times with dichloromethane, the filtrate is concentrated, and the crude product is purified by silica gel column chromatography (petroleum ether / acetone = 3:1, v / v) to obtain compound 26 (34 mg, two-step yield 68%, yellow-brown foamy solid). Optical rotation: [α] D 25 =-188.1(c=0.84,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3)δ7.72(d,J=8.0Hz,2H),7.35(d,J=8.0Hz,2H),6.67(d,J=8.4Hz,1H),6.47(d,J=8.0Hz,1H),4.65(s,1 H),4.22(d,J=6.0Hz,1H),3.87(s,3H),3.74(dd,J=12.8,4.8Hz,1H),3.23(s,1H),3.03(td,J=14.4,5. 2Hz,1H),2.81(dd,J=18.8,6.0Hz,1H),2.72(td,J=12.8,3.6Hz,1H),2.57(d,J=18.4Hz,1H),2.50-2.3 9(m,1H,overlapped),2.46(s,3H),2.29(dt,J=14.4,2.8Hz,1H),1.96-1.88(m,2H),1.70-1.52(m,2H). 13 C NMR (100 MHz, CDCl 3 )δ207.5,145.1,144.1,143.4,136.4,130.1,128.2,127.2,123.2,119.8,115. 4,89.9,70.2,58.7,56.8,50.3,38.6,35.9,31.1,29.4,29.2,21.6.IR(neat):ν max =3492,2929,1726,1504,1440,1278,1157,1048,753cm -1 .HRMS(m / z):[M+H] + calculated for C 24 H 26 NO 6 S + ,456.1475;found,456.1481.

[0150] Example 119 Preparation of compound 29. The synthetic route for compound 29 (oxycodone) is as follows: [ka] Compound 26 (25.0 mg, 0.055 mmol, 1.0 equiv.) was placed in a reaction bottle, ventilated, and protected with argon gas. Dry tetrahydrofuran (2.0 mL) was added, and 0 oCool the mixture to 30°C, add lithium aluminum hydride (1M solution in tetrahydrofuran, 0.28 mL, 0.28 mmol, 5.0 equiv.), and add 40 o The temperature is raised to C and the reaction is continued, and after about 24 hours, TLC detection shows that the raw material reaction is complete. o Cool to 30°C, add isopropanol (19uL), stir for 5 minutes, add water (11uL), stir for 5 minutes, add 15% aqueous sodium hydroxide (11uL) and water (33uL) in sequence, warm the reaction mixture to room temperature and continue stirring for 30 minutes. Filter the resulting mixture through Celite, wash the filter cake with dichloromethane, and concentrate the filtrate under reduced pressure to obtain crude compound 27. Use directly in the next reaction without separation and purification. The crude product 27 was dissolved in methanol (2 mL), and paraformaldehyde (30.0 mg, 0.33 mmol, 6.0 equiv.) was added. The mixture was stirred at room temperature for 2 hours, and then 0 o The reaction mixture was cooled to 0° C., sodium borohydride (17.0 mg, 0.44 mmol, 8.0 equiv.) was added, and the reaction mixture was then warmed to room temperature and reacted for 20 minutes, after which TLC and LC-MS showed the reaction was complete. o Cool to C, quench with saturated aqueous ammonium chloride, dilute the reaction with dichloromethane (2.0 mL), adjust the aqueous layer to pH=9 with 15% aqueous sodium hydroxide, separate the organic layer, extract the aqueous layer with dichloromethane (3 mL×4), combine the organic layers, dry over anhydrous sodium sulfate, filter, and concentrate under reduced pressure. The crude product obtained is used directly in the next reaction without separation and purification. The crude product 28 was dissolved in dichloromethane (2.5 mL) and cooled to 0° C. in an ice bath. o C, Dess-Martin oxidant (70.0 mg, 0.165 mmol, 3.0 equiv.) was added, and the temperature was raised to room temperature. After reacting for 1 hour, the reaction was complete and 0 o Cool to C and add saturated Na 2 S 2 O 3 Aqueous solution and saturated NaHCO 3The reaction is quenched by sequential addition of aqueous solutions, the layers are separated, the aqueous layer is extracted with dichloromethane (3 mL x 4), the organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product is separated and purified by silica gel column chromatography (dichloromethane / methanol, v / v = 20:1) to obtain a white solid 29 (12.0 mg, three-step yield 72%). Mp: 204-206 o C.Optical rotation:[α] D 25 =-205(c=0.28,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ6.70(d,J=8.0Hz,1H),6.63(d,J=8.0Hz,1H),4.66(s,1H),3.90(s,3H),3.15 (d,J=18.8Hz,1H),3.02(td,J=14.4,4.8Hz,1H),2.87(d,J=5.6Hz,1H),2.56(dd ,J=18.8,6.0Hz,1H),2.51-2.36(m,2H),2.41(s,3H),2.29(dt,J=14.4,3.2Hz,1 H),2.22-2.11(m,1H),1.92-1.82(m,1H),1.68-1.61(m,1H),1.61-1.53(m,1H). 13 C NMR(100MHz,CDCl3)δ208.5,145.0,143.0,129.4,124.9,119.4,114.9,90.4,70.4,64.6,56.8,50.2,45.2,42.7,36.1,31.4,30.5,21.9.IR(neat):ν max =3380,2926,1724,1610,1502,1438,1272,1112,1039,941cm -1 .HRMS(m / z):[M+H] + calculated for C 18 H 22 NO 4 + ,316.1543;found,316.1524.

[0151] Example 120 Preparation of compound 32. The synthetic route for compound 32 (naltrexone) is as follows: [ka] Compound 26 (25.0 mg, 0.055 mmol, 1.0 equiv.) was placed in a reaction bottle, ventilated, and protected with argon gas. Dry tetrahydrofuran (2.0 mL) was added, and 0 o Cool the mixture to 30°C, add lithium aluminum hydride (1M solution in tetrahydrofuran, 0.28 mL, 0.28 mmol, 5.0 equiv.), and add 40 o The temperature is raised to C and the reaction is continued, and after about 24 hours, TLC detection shows that the raw material reaction is complete. o Cool to 30°C, add isopropanol (19uL), stir for 5 minutes, add water (11uL), stir for 5 minutes, add 15% aqueous sodium hydroxide (11uL) and water (33uL) in sequence, warm the reaction mixture to room temperature and continue stirring for 30 minutes. Filter the resulting mixture through Celite, wash the filter cake with dichloromethane, and concentrate the filtrate under reduced pressure to obtain crude compound 27. Use directly in the next reaction without separation and purification. The crude product 27 was dissolved in methanol (1 mL), and cyclopropanecarboxaldehyde (17 μL, 0.22 mmol, 4.0 equiv.) was added. The mixture was stirred at room temperature for 3 hours, and then 0 o The reaction mixture was cooled to 0° C., sodium borohydride (13.0 mg, 0.33 mmol, 6.0 equiv.) was added, and the reaction mixture was then warmed to room temperature and reacted for 20 minutes, after which TLC and LC-MS showed the reaction was complete. o The reaction mixture was cooled to C, quenched by adding saturated aqueous ammonium chloride, diluted with dichloromethane (1.0 mL), adjusted the aqueous layer to pH=9 with 15% aqueous sodium hydroxide, separated the organic layer, extracted with dichloromethane (2 mL×4), combined the organic layers, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain crude product 30, which was used directly in the next reaction without separation and purification. Under argon gas protection, the above crude product 30 was dissolved in dry dichloromethane (1 mL) and cooled to 0° C. in an ice bath. oC, Dess-Martin oxidant (47.0 mg, 0.11 mmol, 2.0 equiv.) was added, and the temperature was raised to room temperature. After reacting for 1 hour, the reaction was complete and 0 o Cool to C and add saturated Na 2 S 2 O 3 Aqueous solution and saturated NaHCO 3 The reaction is quenched by sequential addition of aqueous solutions, the layers are separated, the aqueous layer is extracted with dichloromethane (2 mL x 4), the organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product is separated and purified by silica gel column chromatography (dichloromethane / methanol, v / v = 50:1) to obtain compound 31 (15.0 mg, three-step yield 75%). Optical rotation: [α] D 25 =-202(c=0.6,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3 )δ6.69(d,J=8.0Hz,1H),6.61(d,J=8.0Hz,1H),4.67(s,1H),3.89(s,3H),3.18(d,J=6. 0Hz,1H),3.10-2.97(m,2H),2.69(dd,J=12.0,4.8Hz,1H),2.58(dd,J=18.4,6.0Hz,1H) ,2.47-2.37(m,3H),2.30(dt,J=14.4,3.2Hz,1H),2.13(td,J=12.0,4.0Hz,1H),1.92-1 .84(m,1H),1.69-1.54(m,2H),0.93-0.80(m,1H),0.59-0.51(m,2H),0.19-0.10(m,2H). 13 C NMR (150 MHz, CDCl 3 )δ208.5,145.0,142.9,129.5,124.9,119.4,114.9,90.4,70.1,62.1,59.2,56.8,50.8,43.6,36.2,31.5,30.7,22.6,9.4,3.9,3.8.IR(neat):ν max =3381,2928,1726,1502,1439,1278,1258,1048,941,799,748cm -1.HRMS(m / z):[M+H] + calculated for C 21 H 28 NO 4 + ,356.1856;found,356.1857. Under the protection of argon gas, compound 31 (10.0 mg, 0.028 mmol, 1.0 equiv.) was dissolved in dry chloroform (0.6 mL). The reaction solution was cooled to 10°C and BBr 3 Slowly add dropwise a chloroform solution (0.4 mL) of (1M dichloromethane solution, 169 uL, 0.169 mmol, 6.0 equiv.) and keep the temperature constant for 4 hours to react, after which TLC indicates that the raw material has completely disappeared. The reaction solution is added to ice water, alkalized with aqueous ammonia, diluted with a small amount of saturated sodium chloride solution, and extracted with chloroform (2 mL x 10). The organic layers are combined, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The crude product is separated and purified by silica gel column chromatography (dichloromethane / methanol, v / v = 40:1) to obtain a white solid 32 (7.5 mg, 78% yield). Mp: 160-162 o C.Optical rotation:[α] D 25 =-205(c=0.28,CHCl 3 ). 1 H NMR (600MHz, CDCl 3 )δ6.71(d,J=8.0Hz,1H),6.59(d,J=8.0Hz,1H),4.68(s,1H),3.18(d,J=6.0Hz,1H), 3.09-2.99(m,2H),2.70(dd,J=12.0,5.4Hz,1H),2.56(dd,J=18.6,6.0Hz,1H),2.47- 2.37(m,3H),2.32(dt,J=14.4,3.0Hz,1H),2.16(td,J=12.0,3.6Hz,1H),1.92-1.82 (m,2H),1.69-1.52(m,2H),0.94-0.79(m,1H),0.61-0.50(m,2H),0.18-0.10(m,2H). 13 C NMR (150 MHz, CDCl 3)δ209.8,143.4,138.7,129.0,124.3,119.9,117.8,90.6,70.2,62.1,59.2,51.0,43.6,36.2,31.3,30.7,22.6,9.4,4.0,3.8.IR(neat):ν max =3356,2924,1724,1455,1259,1015,796,757cm -1 . HRMS(m / z):[M+H] + calculated for C 20 H 24 NO 4 + ,342.1700;found,342.1702.

[0152] Example 121 Preparation of compound 35. The synthetic route to compound 35 (naloxone) is as follows: [ka] Compound 26 (25.0 mg, 0.055 mmol, 1.0 equiv.) was placed in a reaction bottle, ventilated, and protected with argon gas. Dry tetrahydrofuran (2.0 mL) was added, and 0 o Cool the mixture to 30°C, add lithium aluminum hydride (1M solution in tetrahydrofuran, 0.28 mL, 0.28 mmol, 5.0 equiv.), and add 40 o The temperature is raised to C and the reaction is continued, and after about 24 hours, TLC detection shows that the raw material reaction is complete. o Cool to 30°C, add isopropanol (19uL), stir for 5 minutes, add water (11uL), stir for 5 minutes, add 15% aqueous sodium hydroxide (11uL) and water (33uL) in sequence, warm the reaction mixture to room temperature and continue stirring for 30 minutes. Filter the resulting mixture through Celite, wash the filter cake with dichloromethane, and concentrate the filtrate under reduced pressure to obtain crude compound 27. Use directly in the next reaction without separation and purification. The crude product 27 was dissolved in NMP / H2O under argon gas protection. 2Dissolve in 1H2O (10:1 v / v, 0.55 mL) and add Et3N (15 μL, 0.11 mmol, 2.0 equiv.). Add allyl bromide (7 μL, 0.077 mmol, 1.4 equiv.) slowly to the reaction solution while stirring, then warm the reaction solution to 70 °C and react for 1 hour. After the complete disappearance of the raw material is detected by TLC, the reaction solution is cooled to room temperature, diluted with dichloromethane (2 mL), washed with saturated sodium bicarbonate solution (1 mL × 3), combined with the aqueous layer, extracted once with dichloromethane (3 mL), combined with the organic layer, dried with anhydrous sodium sulfate, and concentrated to obtain crude product 33, which is used directly in the next reaction without separation and purification. The crude product 33 was dissolved in dry dichloromethane (1 mL) and cooled to 0° C. in an ice bath. o C, Dess-Martin oxidant (70.0 mg, 0.165 mmol, 3.0 equiv.) was added, and the temperature was raised to room temperature. After reacting for 1 hour, the reaction was complete and 0 o Cool to C and add saturated Na 2 S 2 O 3 Aqueous solution and saturated NaHCO 3 The reaction is quenched by sequential addition of aqueous solutions, the layers are separated, the aqueous layer is extracted with dichloromethane (2 mL x 4), the organic layers are combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The resulting crude product is separated and purified by silica gel column chromatography (dichloromethane / methanol, v / v = 20:1) to obtain compound 34 (13.7 mg, three-step yield 73%). [α] D 25 =-190.0(c=0.36,CHCl 3 ). 1 H NMR (400 MHz, CDCl 3)δ.6.71(d,J=8.2Hz,1H),6.68-6.61(m,1H),5.96-5.83(m,1H),5.30-5.20(m,2H),4.69(s,1H),3.90(s,3H),3.40-2.96(m,5H),2.7 8-2.57(m,2H),2.56-2.42(m,1H),2.30(dt,J=14.4,3.2Hz,1H),2.20(td,J=12.0,4.0Hz,1H),1.96-1.88(m,1H),1.71-1.53(m,2H). 13 C NMR (100 MHz, CDCl 3 )δ208.3,145.1,143.1,134.0,129.2,124.3,119.5,119.1,90.3,70.3,62.2,57.6,56.8,50.5,43.7,36.0,31.5,30.1,22.8.IR(neat):ν max =3386,2925,1725,1607,1503,1440,1276,1112,1047,940cm -1 .HRMS(m / z):[M+H] + calculated for C 20 H 24 NO 4 + ,342.1700;found,342.1700. Under the protection of argon gas, compound 34 (10.0 mg, 0.029 mmol, 1.0 equiv.) was dissolved in dry chloroform (0.5 mL). The reaction solution was cooled to 10°C and BBr 3 Slowly add dropwise a chloroform solution (0.5 mL) of (1M dichloromethane solution, 176 uL, 0.176 mmol, 6.0 equiv.), and keep the temperature constant for 2 hours to react. TLC indicates that the raw material has completely disappeared. Add the reaction solution to ice water, alkalize with aqueous ammonia, dilute with a small amount of saturated sodium chloride solution, and extract with chloroform (2 mL x 10). Combine the organic layers, dry with anhydrous sodium sulfate, and concentrate to obtain a crude product. The crude product is purified by silica gel column chromatography (dichloromethane / methanol, v / v=20:1) to obtain a white solid 35 (7.2 mg, 76% yield). Mp: 176-177 oC.[α] D 25 =-195.0(c=0.5,CHCl 3 ). 1 H NMR (600MHz, CDCl 3 )δ6.74(d,J=8.0Hz,1H),6.61(d,J=8.0Hz,1H),5.90-5.75(m,1H),5.35-5.10(m,2H),4.69(s,1H),3.30-2.92(m,6H),2.77-2. 51(m,2H),2.50-2.36(m,1H),2.31(dt,J=14.4,3.2Hz,1H),2.17(td,J=12.0,3.6Hz,1H),1.94-1.85(m,1H),1.73-1.48(m,2H). 13 C NMR (150 MHz, CDCl 3 )δ209.7,143.5,138.9,120.0,135.0,128.9,124.0,119.9,118.1,117.9,90.5,70.4,62.2,57.6,50.9,36.1,31.2,30.3,22.8.;IR(neat):ν max =3362,2925,1721,1616,1503,1315,1280,1111,1055,940cm -1 .HRMS(m / z):[M+H] + calculated for C 19 H 22 NO 4 + ,328.1543;found,328.1543. The above is only a preferred embodiment of the present invention, and the present invention is not limited to the form disclosed herein, and should not be considered as excluding other embodiments, particularly the synthesis of other morphine-based drugs from intermediate I, and can be used in various other combinations, modifications and environments. It should be understood that within the concept described in this specification, modifications can be made according to the teachings above or the skills or knowledge of the relevant fields. Modifications and changes made by those skilled in the art shall be within the scope of protection of the claims attached to the present invention, as long as they do not deviate from the spirit and scope of the present invention.

Claims

1. A process for preparing intermediate I, comprising the steps of: S1. 【Chemistry 1】 Compound 18 is provided, and a protecting group R １ to produce compound 19, wherein R １ is a protecting group I for a hydroxy group, and R is a protecting group for a secondary amine; S2. 【Chemistry 2】 the compound 19 is reduced to produce compound 20; S3. 【Chemistry 3】 and preparing compound 20 by a cyclization reaction to produce intermediate I, The synthesis route of compound 18 is as follows: 【Chemistry 4】 In the formula, R ２ is a protecting group II for a hydroxy group, X is a halogen atom, R １１ is a protecting group I for a hydroxy group or a hydrogen atom, R １ is a protecting group I for a hydroxy group, R １１ is a protecting group I for a hydroxy group, the steps of: 1) providing compound 15; 2) removing the protecting group II of the hydroxy group from compound 15 to produce compound 17; 3) compound 17 undergoes an intramolecular oxidative dearomatization Heck reaction to produce compound 18; R １１ is a hydrogen atom, compound 15 is prepared by introducing a protecting group I for a hydroxy group, followed by steps 2) and 3); In step 3), the intramolecular oxidative dearomatization Heck reaction is carried out in the presence of a reactant and a base; the reactants are ligand II and transition metal catalyst II; The ligand II is 【Chemistry 5】 The transition metal catalyst II is PdCl ２ and the molar ratio of the compound 17, the ligand II, the transition metal catalyst II, and the base is 1:0.05-0.5:0.05-0.15:2-4; A process for the preparation of the featured intermediate I.

2. the secondary amine protecting group is selected from one of benzenesulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, methyl, methyl formate, t-butoxycarbonyl, benzyl, benzyloxycarbonyl, trifluoromethanesulfonyl, methanesulfonyl, and trimethylbenzenesulfonyl; A process for the preparation of intermediate I according to claim 1.

3. the protecting group I for the hydroxy group is selected from the group consisting of p-methoxybenzyl, benzyl, acetyl, benzyloxycarbonyl, methoxymethylene, methyl, triisopropylsilyl ether, triethylsilyl ether, and tert-butyldiphenylsilyl; A process for the preparation of intermediate I according to claim 1.

4. In S1, the protecting group R １ the scavenger used for removing is selected from one of sodium hydrogen sulfide, sodium sulfide, sodium ethanethiol, thiophenol, sodium p-toluenesulfonate, potassium fluoride, tetrabutylammonium fluoride, acetic acid, trifluoroacetic acid, hydrobromic acid, iodotrimethylsilane, cerium trichloride, cerium ammonium nitrate, camphorsulfonic acid, p-toluenesulfonic acid, phosphorus oxychloride, 2,3-dichloro-5,6-dicyano-1,4-benzoquinone, and hydrochloric acid; and / or in S1, the protecting group R of the hydroxy group １ the reaction solvent used for removing is selected from the group consisting of N,N-dimethylacetamide, N-methylpyrrolidone, methanol, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane, 1,2-dichloroethane, and acetic acid; A process for the preparation of intermediate I according to claim 1.

5. In S2, the reducing agent for the reduction reaction is selected from one of sodium borohydride, lithium borohydride, lithium aluminum hydride, and lithium tri-tert-butoxyaluminum hydride; And / or in S2, the reaction solvent for the reduction reaction is selected from one or two of methanol, ethanol, tetrahydrofuran, and dichloromethane; And / or, in S2, the reaction temperature of the reduction reaction is −10 to 40° C.; A process for the preparation of intermediate I according to claim 1.

6. In S3, the reaction solvent for the cyclization reaction is selected from the group consisting of N,N-dimethylformamide, N,N-dimethylformamide dimethyl acetal, acetonitrile, tetrahydrofuran, dichloromethane, and 1,4-dioxane; In S3, the cyclization agent of the cyclization reaction is selected from the group consisting of N,N-dimethylformamide dineopentyl acetal, N,N-dimethylformamide dimethyl acetal, N,N-dimethylformamide diethyl acetal, and N,N-dimethylformamide diisopropyl acetal; And / or, in S3, the reaction temperature of the cyclization reaction is 0 to 130° C.; A process for the preparation of intermediate I according to claim 1.

7. the hydroxy-protecting group II is one selected from the group consisting of p-methoxybenzyl, benzyl, acetyl, benzoyl, pivaloyl, tert-butyldimethylsilyl, tert-butyldiphenylsilyl, triisopropylsilyl, and triethylsilyl; A process for the preparation of intermediate I according to claim 1.

8. 2. The method for preparing intermediate I according to claim 1, wherein the halogen atom is one selected from the group consisting of chlorine atom, bromine atom, and iodine atom.

9. In step 2), the removing agent used for removing the protecting group II of the hydroxy group is selected from one or two of potassium carbonate, sodium methoxide, sodium hydroxide, potassium hydroxide, trifluoroacetic acid, hydrochloric acid, boron trichloride, acetic acid, tetrabutylammonium fluoride, tetraethylammonium fluoride, hydrobromic acid, potassium fluoride, and cesium fluoride; and / or in step 2), the reaction solvent used to remove the protecting group II of the hydroxy group is selected from one or two of methanol, N,N-dimethylformamide, acetonitrile, tetrahydrofuran, dichloromethane and water.

10. In step 3), the base is selected from one or two of potassium tert-butoxide, lithium carbonate, sodium carbonate, cesium carbonate, silver carbonate, potassium bicarbonate, potassium carbonate, potassium tetrafluoroborate, potassium phosphate, dipotassium hydrogen phosphate, sodium t-butoxide, lithium t-butoxide, sodium hydride, potassium hydride, sodium acetate, sodium methoxide, sodium benzoate, potassium benzoate, pyridine, triethylamine, diisopropylethylamine, cesium fluoride, potassium hydroxide, and pivalate; and / or in step 3), the reaction solvent for the intramolecular oxidative dearomatization Heck reaction is selected from the group consisting of anisole, trifluoromethylbenzene, N,N-dimethylformamide, N,N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, trimethylbenzene, dimethyl ether, ethanol, tert-butyl alcohol, toluene, chlorobenzene, xylene, 1,4-dioxane, diethylene glycol dimethyl ether, methyl tert-butyl ether, tetrahydrofuran, and ethylene glycol dimethyl ether; and / or in step 3), the concentration of compound 17 in the intramolecular oxidative dearomatization Heck reaction is 0.05-2.5 mol / L; And / or, in step 3), the reaction temperature of the intramolecular oxidative dearomatization Heck reaction is 50-160° C.; A process for the preparation of intermediate I according to claim 1.

11. In step 3), the base is potassium phosphate and potassium carbonate; And / or in step 3), the reaction solvent is one of N,N-dimethylformamide, N,N-dimethylacetamide and anisole; and / or in step 3), the concentration of compound 17 in the intramolecular Heck reaction is 0.05-1 mol / L; and / or in step 3), the reaction temperature of the intramolecular Heck reaction is 60 to 150° C.; A process for the preparation of intermediate I according to claim 10.

12. The synthesis route of compound 15 is as follows: 【Chemistry 6】 In the formula, R ２ is a protecting group II for a hydroxy group, and R ２２ is a protecting group II for a hydroxy group or a hydrogen atom, X is a halogen atom, R １１ is a protecting group I for a hydroxy group or a hydrogen atom, R ２２ is a protecting group II for a hydroxy group, a. providing compound 11; b) reacting compound 11 with Bischler-Napieralski to obtain compound 13; c) asymmetric transfer hydrogenation of compound 13 to obtain chiral tetrahydroisoquinoline type compound 14; d. secondary amine protection of compound 14 to produce compound 15; R ２２ is a hydrogen atom, the compound 11 is further subjected to steps b, c and d after introducing a protecting group II of a hydroxy group; A process for the preparation of intermediate I according to claim 1.

13. The method for preparing intermediate I according to claim 12, characterized in that in step b, the Bischler-Napieralski reaction is carried out in the presence of a condensing agent and a base, and the molar ratio of compound 11 to the condensing agent and the base is 1:0.9-1.3:1.5-2.

5.

14. the condensing agent is one selected from phosphorus oxychloride, diphosphorus pentaoxide, and trifluoromethanesulfonic anhydride; and / or in step b, the base is selected from the group consisting of 2-fluoropyridine, pyridine, 4-dimethylaminopyridine, dimethyl pyridine and triethylamine; And / or in step b, the reaction solvent of the Bischler-Napieralski reaction is selected from one of dichloromethane, dichloroethane, tetrahydrofuran and toluene; and / or in step b, the temperature of the Bischler-Napieralski reaction is −50 to 40° C.; A process for the preparation of intermediate I according to claim 13.

15. 13. The method for preparing intermediate I according to claim 12, wherein in step c, the asymmetric transfer hydrogenation reaction is carried out in the presence of chiral ligand I, hydrogen source I and metal catalyst I, and the molar ratio of compound 13, metal catalyst I, chiral ligand I and hydrogen source I is 1:0.001-0.01:0.002-0.02:1.2-3.

16. In step c), the chiral ligand I is 【Chemistry 7】 and / or in step c, the hydrogen source I is selected from the group consisting of formic acid, ammonium formate, and a complex of formic acid with a trialkylamine; and / or in step c) said metal catalyst I is 【Chemistry 8】 and / or in step c, the reaction solvent for the asymmetric hydrogenation reaction is selected from one of dichloromethane, dichloroethane, chloroform, tetrahydrofuran, dimethyl ether, tert-butyl methyl ether, trifluoroethanol, anisole, N,N-dimethylformamide, trifluoromethylbenzene, N,N-dimethylacetamide, dimethylsulfoxide, N-methylpyrrolidone, trimethylbenzene, ethanol, tert-butyl alcohol, toluene, chlorobenzene, xylene, 1,4-dioxane, dichlorobenzene, hexafluoroisopropanol, methanol, and isopropanol; and / or in step c, the temperature of the transfer hydrogenation reaction is −10 to 40° C.; A process for the preparation of intermediate I according to claim 15.

17. In step c, the hydrogen source I is a methanol and triethylamine complex; and / or in step c, the reaction solvent is N,N-dimethylformamide; and / or in step c, the temperature of the transfer hydrogenation reaction is 0-35° C.; 17. A process for the preparation of intermediate I according to claim 16.

18. In step d, secondary amine protection is carried out under basic conditions, the base used in the basic conditions is selected from the group consisting of disodium hydrogen phosphate, sodium dihydrogen phosphate, potassium carbonate, sodium carbonate, triethylamine, N,N-diisopropylethylamine, pyridine, and 4-dimethylaminopyridine; A process for the preparation of intermediate I according to claim 12.

19. The preparation method of compound 11 includes the following steps: Compound 9 and compound 5 are provided, and compound 11I is obtained by amine acid condensation reaction. The reaction scheme is as follows: 【Chemistry 9】 Here, R ３ is a methyl group or a hydrogen atom, X is a halogen atom, R ２２ is a hydrogen atom or a protecting group II of a hydroxy group, A process for the preparation of intermediate I according to claim 12.

20. The amino acid condensation reaction is carried out in the presence of a condensing agent and a base, the molar ratio of the compound 9, the compound 5, the condensing agent and the base is 1-1.6:1:1-1.2:1.5-3; 20. A process for the preparation of intermediate I according to claim 19.

21. The condensing agent is selected from the group consisting of O-1H-benzotriazole-N,N,N',N'-tetramethylurea tetrafluoroboric acid, 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride, 2-(7-azabenzotriazole)-N,N,N',N'-tetramethylurea hexafluorophosphate, dicyclohexylcarbodiimide, and 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate; and / or the base is selected from the group consisting of triethylamine, N,N-diisopropylethylamine, 4-dimethylaminopyridine and pyridine; and / or the temperature of the amine acid condensation reaction is −10 to 50° C.; 21. A process for the preparation of intermediate I according to claim 20.

22. R in the compound 11I ３ is a protecting group R of a hydroxy group １ to give compound 11II, the reaction scheme being as follows: 【Chemistry 10】 In the formula, R １ is a protecting group I for a hydroxy group, and R ２ is a protecting group II for a hydroxy group, 20. A process for the preparation of intermediate I according to claim 19.

23. The method for preparing compound 9 includes the steps of: 【Chemistry 11】 A. Providing compound 6; B. reacting compound 6 with nitromethane via Henry reaction to produce compound 7; C. Compound 7 is subjected to a double bond reduction reaction to produce compound 8; D. reacting compound 8 with nitro to produce compound 9I, 20. A process for the preparation of intermediate I according to claim 19.

24. Compound 9I can be further converted to compound 9II by hydroxyl group protection reaction, and the reaction scheme is as follows: 【Chemistry 12】 Here, R ２ is a protecting group II for a hydroxy group, 24. A process for the preparation of intermediate I according to claim 23.

25. The method for producing compound 5 includes the steps of: 【Chemistry 13】 and In the formula, R ３ is a methyl group or a hydrogen atom, (1) providing compound 1; (2) subjecting compound 1 to a halogenation reaction to produce compound 2; (3) subjecting compound 2 to a Wittig reaction to produce compound 3; (4) hydrolyzing the compound 3 to produce a compound 4; (5) a step of oxidizing the compound 4 to produce a compound 5, 20. A process for the preparation of intermediate I according to claim 19.

26. The morphine derivative includes one of codeine, oxycodone, hydrocodone, buprenorphine, naloxone, naltrexone, and nalbuphine; 26. The use of the process for the preparation of intermediate I according to any one of claims 1 to 25 in the preparation of morphine and morphine derivatives.

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